Manuel was born in Virginia Beach, Virginia. He attended Bayside High School Virginia Beach, where he played for the Bayside Marlins high school football team. In 2004, as a freshman, he started at quarterback and threw for 589 yards and seven touchdowns, as well as rushing for 219 yards and one touchdown. As a sophomore, he recorded 1,332 passing yards and eight touchdowns as well as 276 rushing yards and six touchdowns. As a junior, Manuel threw for 1,973 yards and 15 touchdowns while rushing for 345 yards and five touchdowns. In 2007, as a senior, Manuel passed for 1,859 yards, 18 touchdowns while rushing for 541 yards. He was considered a five-star recruit by Scout, a four star recruit by Rivals and both sites, as well as Sports Illustrated, listed him the second best quarterback. He was an All-American quarterback in high school.
Manuel enrolled in Florida State University, where he played for coach Bobby Bowden and coach Jimbo Fisher's Florida State Seminoles football teams from 2008 to 2012. While he was a student, he joined the Pi Kappa Alpha Fraternity. Manuel became the second collegiate quarterback to win four straight bowl games, the first being Pat White of West Virginia (2005-2008).
Manuel took over for an injured Christian Ponder as the 4-5 Seminoles were in danger of finishing with a losing record for the first time since Bobby Bowden took over the program. His first start was an away game against Wake Forest. He completed 15-of-20 passes for 220 yards with one touchdown, leading the Seminoles to a 41-28 win over Wake Forest, who at the time had won three games in a row against Florida State. Manuel struggled in his second game against Maryland but still managed to pull out a much needed win making FSU bowl-eligible. Manuel's struggles continued against the dominating Florida Gators, and the mobile quarterback was not able to get into a rhythm as Florida State lost by a score of 37-10.
Florida State entered the Gator Bowl 6-6 and in serious danger of letting legendary coach Bobby Bowden leave with a losing record. Manuel led Florida State to a 33-21 victory over the West Virginia Mountaineers and won the Gator Bowl MVP honors.
Manuel started twice in the 2010 season in relief of Christian Ponder, who battled a nagging forearm injury. In his first start against Clemson, he picked up 71 yards on 15 carries. He also led the Seminoles to a victory in the 2010 Chick-fil-A Bowl against South Carolina in relief of Christian Ponder, who injured in the second quarter of the game.
In the 2011 season, Manuel played in every game besides the loss at Clemson after injuring his shoulder in a loss against Oklahoma the previous week. He finished the season with 2,666 yards passing on a 65% completion rate. He also finished with 18 passing touchdowns, four rushing touchdowns, and eight interceptions. He helped lead the Seminoles to a comeback win against the Notre Dame Fighting Irish in the Champs Sports Bowl by throwing for 249 yards and two touchdowns.
In the 2012 season, Manuel led the Seminoles to numerous wins over ACC rivals, an ACC Championship, and an Orange Bowl win against Northern Illinois for a 12-2 record in his senior season.
Manuel led the Seminoles to a 12-win season for just the third time in program history and the first time since their dominant stretch in the 1990s. During his senior season, he threw for the second most yards in team history with 3,392, trailing only Chris Weinke's Heisman Trophy winning season, in which Weinke threw for 4,167 yards. Manuel went 25-6 as a starter, won the first BCS bowl for Florida State since 2000, won five out of six games against intrastate rivals Miami and Florida, and he led the offense to its most prolific season in team history, cleanly surpassing the 1999 National Championship squad with 6,591 yards.
NFL.com analyst Bucky Brooks projected him as a top five quarterback heading into the 2013 Draft and compared him to Josh Freeman. While Manuel possesses the blue-chip physical characteristics, work ethic, and leadership qualities necessary to be successful at the NFL level, he was faulted for somewhat inconsistent play at times during his college career.
Manuel was selected by the Buffalo Bills in the first round with the 16th overall pick in the 2013 NFL Draft. Manuel was the only quarterback taken in the first round of the draft, a draft that was seen as especially thin at quarterback (the Bills, who originally drafted eighth and had a great need for a quarterback, even traded down to obtain more picks); Manuel was drafted ahead of Matt Barkley and Geno Smith, as well as Ryan Nassib, who had played under Bills head coach Doug Marrone when Marrone coached the Syracuse Orange.
On June 14, 2013, Manuel signed a four-year contract with the Buffalo Bills. The deal is worth a fully guaranteed $8.88 million, including a signing bonus of $4.85 million evenly spaced out annually ($1.2 million) over the next four years. His salary in 2013 will be $1.6 million, $2.0 million in 2014, $2.4 million in 2015, and $2.8 million in 2016.
Manuel made his professional debut on August 11, 2013, during the preseason against the Indianapolis Colts, completing 16-of-21 passes for 107 yards and a touchdown. Manuel underwent an operation on his knee to remove fluid buildup after the second game of the preseason and it was unsure if he would be ready to start the 2013 regular season opener. On September 4, 2013, Doug Marrone announced at the team meeting that Manuel was confirmed to be the starter for Week 1. In the season opener, Manuel completed his first touchdown to fellow rookie Robert Woods, on an 18-yard completion. On September 16, Manuel engineered his first fourth quarter comeback, with a nine-play, 80-yard touchdown march to bring his team from a six-point deficit in the fourth quarter with seconds left in the game. The Buffalo Bills went on to win in a Week 2 game against the Carolina Panthers by a score of 24-23. Manuel was voted the "Pepsi Next NFL Rookie of the Week" for his performance.
On October 3, 2013, during the third quarter against the Cleveland Browns, Manuel sprained the lateral collateral ligament in his right knee. The injury caused him to miss the next five weeks of his rookie season. Manuel had an up and down first year, but was given a vote of confidence by coach Doug Marrone as he was announced as the starting quarterback for the 2014 season.
On September 28, 2014, in a game against the Houston Texans, one of Manuel's passes was intercepted by All-Pro defensive end J. J. Watt and returned 80 yards for a touchdown. The next day, Manuel was benched in favor of veteran quarterback Kyle Orton after starting the first four games of the 2014 season and bringing the Bills to a 2-2 record. Orton would win seven of the next 12 games, finishing the Bills 2014 season with a 9-7 record, the first time the team had posted a winning record since 2004.
After posting the franchise's first winning record in a decade, Orton retired and Marrone opted out of the rest of his contract. The Bills then hired former division rival Rex Ryan as head coach. Manuel competed with free agent acquisition Tyrod Taylor and trade acquisition Matt Cassel for the starting quarterback job. During mini-camp, Manuel struggled to compete for the starting job and was listed as the number three quarterback on the depth chart. Manuel performed well in the third preseason game, completing nearly all of his passes, showing he had improved his accuracy. On August 31, 2015, coach Rex Ryan announced that Manuel and Cassel lost the starting job to Taylor.
Manuel made his first start in over a year in Week 6 against the undefeated Cincinnati Bengals in place of injured Tyrod Taylor, who suffered a MCL injury the previous week. On the first drive of the game for the Bills against the Bengals, Manuel led the Bills 80 yards down the field for a touchdown. Manuel finished 28-for-42 passing with 263 passing yards, a passing touchdown, one touchdown rushing, and an interception in the 34-21 loss.
Against the Jacksonville Jaguars on October 25 in London, Manuel threw for 298 yards and two touchdowns but had three costly turnovers, two of which were returned directly for scores by the Jacksonville defense in the second quarter. He rallied the Bills from 24 points down to take the lead in the fourth quarter. However, Jacksonville regained the lead with a Blake Bortles touchdown pass to wide receiver Allen Hurns, sealing the win 34-31 as the Bills were unable to respond. With the loss, Manuel became the first quarterback in NFL history to lose a game in three different countries (United States, Canada, England).
On May 2, 2016, it was announced that the Buffalo Bills declined to exercise his fifth-year option for the 2017 season. Manuel would see spot duty through the first part of the 2016 season, usually as parts of trick plays. With the Bills being out of playoff contention, Manuel started the final game of the regular season due to Tyrod Taylor being inactive. He completed 9 of 20 passes for 86 yards before being benched for rookie Cardale Jones to start the fourth quarter.
On March 20, 2017, Manuel signed with the Oakland Raiders.
It was reported that Manuel would be offering stock in his future earnings via a venture with Fantex, Inc. as part of a new financial instrument being sold by Fantex. Manuel planned to offer a 10% share of all future earnings from his brand to Fantex, which would then turn around and divide it into shares of a publicly traded tracking stock.
In July 2014, the Manuel/Fantex stock offering was completed. 523,700 shares were sold, valued at $10 per share.