Moore played high school basketball at Central High School in East Chicago, where he averaged 21.2 points, 5.5 rebounds and 3.3 assists per game during his senior year. That same season, along with 6'11" teammate Ángel García and future Carolina Panther Kawann Short, Moore led his team to the 2007 Indiana High School Athletic Association 4A State Championship, scoring 28 points against Indianapolis North Central High School, which starred 2007 Indiana Mr. Basketball and current NBA player, Eric Gordon. Moore earned the tournament's Trester Award. Moore was named to the Indiana All-Star Team, and was also honored as a third-team Parade All-American.
Moore was ranked as the number eight high school basketball shooting guard in the nation by Scout.com. Rivals.com ranked him as the number seven shooting guard in the nation, the second best player in Indiana (to Gordon) and the 35th best player in the nation. Hoopmaster.com ranked him as the 26th best player in the nation, sixth best shooting guard and second best Indianan. ESPN evaluated him as a point guard and rated him as the 4th best point guard and 20th best player in the nation.
He received scholarship offers from Illinois, Indiana, Iowa, Miami, Tennessee, and Virginia Tech. Following Indiana's struggles with head coach, Mike Davis' resignation, Purdue swept the best talent from the Indiana class of 2007. Moore was expected to make the transition to the next level and contribute immediately. As a top 40 recruit, he joined Robbie Hummel, Scott Martin and JaJuan Johnson as part of the nations number 5 and 6 ranked recruiting class according to Scout.com and Rivals.com, respectively. Moore, Hummel and Martin were teammates in the Amateur Athletic Union (AAU) basketball program and were united with Johnson on the Indiana State All-Star squad.
Moore attended Purdue University to play under head coach Matt Painter. He became roommates with fellow freshman teammate, Robbie Hummel, and shared a common bathroom with JaJuan Johnson and Scott Martin. On February 4, 2008, Moore was named co-Big Ten Player of the Week for his efforts against the Iowa Hawkeyes and the Illinois Fighting Illini on January 30 and February 2. He led the "baby boilers" in scoring with 12.9 points a game, becoming the first true freshman in Boilermaker history to lead in that category. He broke the Purdue freshmen record with most three point field goals made with 66. Chris Lutz had previously set the record for the 2006 team when he finished with 53. He also reached second place among Purdue Freshmen in total points scored with 437 behind Russell Cross' 540. Moore helped lead Purdue to a 2nd straight NCAA Tournament appearance, losing to a senior-led Xavier team in the Second Round after defeating the Baylor Bears, and led the Boilers to a 25–9 overall record. He was named a Second Team All-Big Ten selection, while selected to the Big Ten All-Freshmen Team.
Moore finished his sophomore season for the 2008–09 Boilermakers as the leading scorer for the team again and ranked second in assists as well as third in rebounds. He earned his second conference player of the week award on December 1, 2008, following his performance in the final week of the 2008 NIT Season Tip-Off, where he helped Purdue finish second in the 16-team field. In the semifinals at Madison Square Garden, he led the team to a 71–64 victory of Boston College with 19 points. Then, in the championship game, he helped the team reach overtime against Oklahoma despite Blake Griffin's double double by scoring 22 points. He scored in double figures 30 times (23–7), including three 20+ point performances (1–2). He helped lead the Boilers to an 11–2 preseason record and an 11–7 record in conference play. Moore scored a season high 26 points against Indiana and recorded two double-doubles in league play. He was named Second Team All-Big Ten. He was also recognized as a Conference All-Academic selection. He helped lead Purdue to its first Big Ten Tournament Championship in school history and was one of three Boilers to be named to the all-conference tournament team. Moore then led them to the program's 2009 NCAA Tournament, its third straight appearance and onto its first Sweet Sixteen appearance in 9 years. Moore played in 1,222 minutes on the season, the second most in school history behind Joe Barry Carroll's 1,235 in the 1979–80 season. The 37 games in which he appeared in is a season-school record, which he shares with JaJuan Johnson, Marcus Green and Keaton Grant.
To start the 2009–10 season, Moore was named a preseason candidate for the John R. Wooden Award along with teammate, Robbie Hummel. With a 22-point performance against Tennessee and being named the 2009 Paradise Jam Tournament MVP, he became the 43rd Boilermaker to score his 1,000th career point. He helped lead Purdue to a 14–0 season start, which tied the Glenn Robinson-led 1993–94 team as the best start in school history. He was named to the District 5 First Team Academic All-District Team, as selected by ESPN The Magazine and College Sports Information Directors of America, making him one of 40 finalists for the 15-man Academic All-American team, in which he was eventually selected as a Second Team Academic All-American. E'Twaun had a 28-game double-digit scoring streak that extended from November 20 – March 3. The streak consisted of eight 20+ point performances, which included a career high 28 points on March 12, 2010, in the quarterfinals of the 2009 Big Ten Conference Men's Basketball Tournament against Northwestern. Leading Purdue in scoring with 16.5 points a game and shooting beyond the arc at 34.3 percent, he was also second on the team with 2.7 assists per outing behind Lewis Jackson's 3.5 mark. With a 14–4 record in conference play, Moore helped Purdue to its share of the first Big Ten Conference regular season title in fourteen years. Moore was named a First Team All-Big Ten selection by both the coaches and the media at the conclusion of the regular season. He was selected by the U.S. Basketball Writers Association to the 10-man All-District V team covering college basketball players in the states of Ohio, Indiana, Illinois, Michigan, Minnesota, and Wisconsin. Moore was a Third-Team All-American selection by Yahoo! Sports and an Honorable Mention All-American by the Associated Press., while being recognized as an All-District First-Team selection by the National Association of Basketball Coaches. Moore led Purdue to a 4 seed in the NCAA Tournament, culminating with a consecutive Sweet Sixteen after beating Siena and Texas A&M. Eventually losing to Duke for the second time in his career, he led Purdue to a 29–6 record, which tied for the most season wins in school history. He concluded the season sixth in the Big Ten Conference in scoring (teammates Hummel and Johnson finished seventh and eighth) and ninth in steals. With 93 assists to go along with his scoring, he is only the third boilermaker to lead the team in total points and assists since Larry Weatherford did in the 1970–1971 season. He is the first person to lead the team in scoring three straight seasons since Troy Lewis did in the late-eightees. He earned repeat recognition as an Academic All-Big Ten selection.
After being named First Team All-Big Ten in his junior season, Moore decided to enter the 2010 NBA Draft along with teammate JaJuan Johnson. On the deadline of May 8, both players decided to pull out of the draft and return for their senior seasons. E'Twaun began his senior season as a Preseason First Team All-Big Ten selection by the Big Ten media for the 2010–11 Big Ten Conference men's basketball season., a preseason top 50 candidate for the Wooden Award and a candidate for the Lowe's Senior CLASS Award. On November 26, 2010, Moore recorded his first 30-point game performance when he scored 31 points by going 9 of 18 from the floor against Southern Illinois. E'Twaun had another 31 point performance New Year's Eve against Northwestern, which included a career-high of 7 made three-point field goals in a game. He recorded season highs of 7 assists against Alcorn State on November 17, 9 rebounds (4 times), and 4 steals against Austin Peay. On January 3, he was named Co-Big Ten Player of the Week. In early-mid January, Moore went cold, making only 15 of his 57 shot attempts from the floor, while not attempting a single free throw in four games (2–2). On February 20, Moore led #11 Purdue with a career-high 38 points over #3 Ohio State, which included a career-high 7 three-point field goals, while scoring his 2,000th career point. It was the most points scored by a Boilermaker in a single game since Glenn Robinson in 1994. The performance earned Moore Big Ten Player of the Week recognition. Moore was named one of ten finalists for the Lowe's Senior Class Award, as well as selected to both the midseason Naismith Award and midseason Wooden Award top-30 lists. Moore helped lead #9 Purdue to a 2nd-place finish in conference play with a 14–4 record and 25–6 overall. Moore was again selected for the First-Team All-Big Ten along with teammate JaJuan Johnson. Moore was also a National Association of Basketball Coaches (NABC) Division I District 7 All‐District second team choice. Since the Big Ten Conference was its own district, this is equivalent to being named second team All-Big Ten by the NABC. Moore was selected by the United States Basketball Writers Association to its 2010–11 Men's All-District Team. Moore was among the 20 players on the final ballot for the John R. Wooden Award. Moore finished his senior year averaging career highs of 18 points (2nd on team), 5.1 rebounds (2nd), 3.2 assists (2nd), and .5 blocks. He shot 44.7 from the floor, 71 percent from the line, and 40 percent from beyond the arc. He scored 20+ points in eleven games, including three 30+ point games. The National Association of Basketball Coaches named Moore a third team All-American Selection, and he was picked as a Third Team All-American by Fox Sports. The Associated Press named Moore an honorable mention.
E'Twaun Moore became the third player in Big Ten history to tally 2,000 points (2,136), 500 rebounds (611), and 400 assists (400) in a career, joining Michigan State's Steve Smith, and Penn State's Talor Battle. He left Purdue being the third highest scorer, trailing only Rick Mount and Joe Barry Carroll. E'Twaun holds program records with most minutes played (4,517), three-point field-goals made (243), games won (107), games played (140), and starts (137). He led Purdue in scoring in each of his first three seasons (2008, 2009, 2010). Moore had career averages of 15.3 points, 4.4 rebounds, 2.9 assists, 1.2 steals, .5 blocks, and shot 44 percent from the field, 73 percent from the line, and 38 percent beyond the arc during his time at Purdue.
Moore was selected with the 55th overall in the 2nd round of the 2011 NBA Draft by the Boston Celtics. Due to the lockout, Moore signed a deal with Italy's Benetton Treviso that featured an opt-out clause that let him return to the Celtics once the lockout ended. On December 9, 2011, Moore signed a guaranteed contract with the Celtics. He debuted briefly (for less than 1 minute) in the Celtics' season-opener against the New York Knicks on Christmas Day. He posted his first rebound and assist on December 28 against the Charlotte Bobcats. He scored his first points on January 4, 2012, against the New Jersey Nets. He got significant minutes for the first time in a game against the Indiana Pacers at Bankers Life Fieldhouse in his home state, when he played 20 minutes. In the subsequent weeks with Keyon Dooling and Sasha Pavlović injured he often received a significant amount of playing time. He recorded 16 points on January 26, 2012, against the Orlando Magic, going 4–4 from distance. On April 24, Moore established a career high of 7 rebounds against the Miami Heat.
On July 20, 2012, Moore was traded to the Houston Rockets in a three team deal between the Celtics, Rockets and Portland Trail Blazers that sent Moore, JaJuan Johnson, Sean Williams and Jon Diebler to the Rockets, Courtney Lee to the Celtics and Sasha Pavlović to the Trail Blazers . He was waived by the Rockets shortly afterwards. On September 6, 2012, he signed with the Orlando Magic. With Jameer Nelson and Hedo Türkoğlu beginning the season injured for the 2012–13 Orlando Magic, Moore began the 2012–13 NBA season as a starter. Moore posted a career-high 17 points on November 6, 2012, against the Chicago Bulls. He topped this with 18 points on November 6 against the Brooklyn Nets. Nelson returned to the starting lineup on November 16 after missing the first six games of the season. On December 28, Moore suffered an elbow sprain when he and Cartier Martin landed on his arm during a loose ball scramble against the Washington Wizards. The injury made his status day-to-day. Moore was unable to play the following night. He did not practice with the team again until January 13. Moore returned to the lineup the following day. He again scored 18 points to tie his career high on January 28 against the Detroit Pistons. When Nelson incurred a bruised left forearm, Moore returned to the starting lineup on February 2 against the Milwaukee Bucks. As a starter on February 4, he again tied his career high with 18 points against Philadelphia 76ers. Although Nelson returned to the starting lineup after two starts, J. J. Redick was injured prior to the game on February 4 and Arron Afflalo continued to be injured, necessitating Moore's continued role as a starter. On February 13, both Redick and Afflalo returned to the lineup, relegating Moore to a reserve role. On February 21, the Magic traded away Redick, and Nelson was diagnosed with a strained left knee patella tendon. Thus, Moore returned to the starting lineup on February 22. On March 1, Moore posted a career-high 11 assists against the Houston Rockets. On March 5, Nelson returned to the starting lineup.
For the first 15 games of the 2013–14 NBA season, Nelson started at point guard for the Orlando Magic, but on November 29, he missed the game due to injury. Victor Oladipo moved from shooting guard to point guard, while Moore became the starting shooting guard against the San Antonio Spurs. Moore missed some action due to injury with the game against Sacramento on December 21. He returned to the lineup three games later on December 29. On February 18 against the Milwaukee Bucks, Moore had 17 points and 2 blocks, which were season highs. Moore tied his season high of 17 points on 6-for-6 shooting, including 5-for-5 on three point shots on April 9 against the Brooklyn Nets.
On September 18, 2014, Moore signed with the Chicago Bulls. With injuries sidelining Derrick Rose, Jimmy Butler and Taj Gibson on March 5, 2015, Moore scored a career-high 19 points and hit the game winning three-point shot with 2.1 seconds remaining to help the Bulls defeat the Oklahoma City Thunder 108-105. On January 14, 2016, with Rose again sidelined, Moore scored Chicago's first 7 points in overtime as the Bulls overcame both a 24-point deficit and a 4-point overtime deficit to defeat the Philadelphia 76ers. Starting in place of Butler on February 3, Moore posted a career-high 24 points, including 13 points on 5-for-5 shooting in the first half, against the Sacramento Kings. On February 21 against the Los Angeles Lakers, Moore scored 24 points again on the night that Kobe Bryant made his farewell visit to the United Center.
On July 21, 2016, Moore signed with the New Orleans Pelicans. On October 26, Moore began the season with a 10-point performance as a starter in his debut for the Pelicans, but missed a game-tying three point shot attempt with 24 seconds left.
Moore was born in East Chicago, Indiana to parents Ezell and Edna Moore. He has a brother, Ezell and a sister, Ekeisha.