Plumlee first attended Warsaw Community High School in Warsaw, Indiana before transferring to Christ School in Arden, North Carolina after his freshman year. Following the transfer of Mason and his siblings, a town hall meeting was held to consider removing Warsaw's head basketball coach Doug Ogle for the Plumlee brothers transfer, among other factors (Ogle retained his job and later led Warsaw to a state runner-up championship in 2009–10). At Christ School, Mason helped lead the team to three North Carolina High School Athletic Association state championships and a record of 99–8 over his last three years. He earned a silver medal with the 2008 USA U18 National Team at the FIBA Americas Under-18 Championship. Plumlee was named a 2009 McDonald's All-American as a senior after he averaged 15.3 points, 10.1 rebounds, 3.3 assists, and 2.5 blocks per game for the year, a Jordan Brand All-American, and a third-team Parade All-American and Slam All-American. He was named 2009 North Carolina Mr. Basketball by the Charlotte Observer, and was twice an All-State pick. In addition, he competed in the high jump in track and field, with an individual best jump of 6 feet 8 inches.
His brother Miles had originally committed to play at Stanford, but chose to follow him to Duke after Stanford coach Trent Johnson left for LSU. Mason was elated, as they had been in boarding school together, and never really spent much time apart.
He missed the first six games of the 2009–10 season with a broken left wrist. He and Miles usually rotated into games together, replacing Brian Zoubek and Lance Thomas, and were often the first two players off the bench. Teammate Nolan Smith said: "He's an athlete. He can run and jump with the best of them in the country."
Through April 4, 2010, Mason was tied for first on the team in blocks, with 30, and second on the team with 21 dunks. In an average 14.1 minutes of play per game during the 2009–10 season, he averaged 3.1 rebounds and .9 blocks.
Coach Mike Krzyzewski said: "Mason has got a chance to be really, really good. He has skills of a guard and the body of a big man, and a great basketball mind. He's very competitive, he likes the stage, and he's comfortable with the ball."
It was anticipated that in 2010–11 the two brothers would both be in Duke's starting lineup. Georgia Tech coach Paul Hewitt viewed Mason as Duke's best pro prospect. Told in early April 2010 that some scouting services viewed him as the team's best pro prospect, Plumlee said: "I have seen that. I don't even really know what to say to those people. I mean, let's be real. I'm trying to play the best I can, but in reality nobody goes from the bench to the NBA. Come on."
Mason started 11 of the team's first 13 games in the 2010–2011 season, in 3 of which he recorded double doubles in points and rebounds. For the season, he averaged 7.5 points, 8 rebounds, and 1.5 blocks per game to help man the paint for the defending champion Blue Devils.
He was a 2012–13 first team Academic All-American selection. He was also a 2012–13 Senior CLASS Award finalist.
Plumlee was selected with the 22nd overall pick by the Brooklyn Nets in the 2013 NBA draft. On July 3, 2013, he signed his rookie-scale contract with the Nets. On November 15, 2013, in his first game against his brother Miles and the Phoenix Suns, he recorded 7 points, 3 rebounds and 2 assists in a 100-98 overtime win. The following night, Plumlee played 26 minutes against the Los Angeles Clippers with both Brook Lopez and Kevin Garnett out injured, and had 19 points and 6 rebounds, both career highs. Plumlee was selected to play in the 2014 BBVA Rising Stars Challenge on Chris Webber's team, while his brother Miles was picked to play on Grant Hill's team. February 9, 2014 Plumlee recorded his second NBA double-double, finishing with 22 points and 13 rebounds in a Nets victory. On March 17, 2014, both Miles and Mason Plumlee started for the Suns and the Nets, respectively. Mason had 14 points and 11 rebounds, while Miles had 3 points and 6 rebounds in a 108-95 Nets win.
On April 8, 2014, the Nets faced the two-time defending champion Miami Heat, looking to become the first team to sweep LeBron James in a four-game season series. With Kevin Garnett resting his back and Andray Blatche out with illness, Plumlee was the only active center on the Nets roster. The Nets held an 88-87 lead in the closing seconds when James attempted a dunk that would have won the game for the Heat. Plumlee blocked the shot and secured the season sweep in what the New York Times described as a signature moment in his career. Although James was visibly upset about the play, and claimed that he had been fouled, the NBA later announced that the call was correct and that the block was clean. In 70 games (22 starts), he averaged 7.4 points and 4.4 rebounds per game as he earned NBA All-Rookie first team honors, becoming the first Net since Brook Lopez (2008–09) to earn such honors.
Following the departure of Andray Blatche, Plumlee came into the season as the primary back-up to Brook Lopez. On October 24, 2014, the Nets exercised their third-year team option on Plumlee's rookie scale contract, extending the contract through the 2015–16 season.
After starting the first two games of the season in the absence of Lopez, Plumlee moved back to a bench role in the wake of Lopez's return until the starting center once again missed time during December, in which Plumlee was put back into the starting line-up. He subsequently scored a season-high 18 points and added 10 rebounds on December 12 in helping the Nets defeat the Philadelphia 76ers, 88–70. He surpassed his season high on December 23 with 19 points, while also grabbing a career-high 13 rebounds, in a 102–96 win over the Denver Nuggets. On January 12, 2015, he surpassed his season high again with a career-high 24 points in a 113–99 loss to the Houston Rockets.
On June 25, 2015, Plumlee was traded, along with the draft rights to Pat Connaughton, to the Portland Trail Blazers in exchange for Steve Blake and the draft rights to Rondae Hollis-Jefferson. On September 30, the Trail Blazers exercised their fourth-year team option on Plumlee's rookie-scale contract, extending the contract through the 2016–17 season. On December 14, he recorded 15 points, 13 rebounds and a then career-high six assists in a 105–101 win over the New Orleans Pelicans. On January 6, he scored a season-high 19 points in a loss to the Los Angeles Clippers. On January 18, he recorded his 12th double-double of the season with 10 points, 11 rebounds and a career-high seven assists in a 108–98 win over the Washington Wizards. On January 29, in a win over the Charlotte Hornets, Plumlee recorded 13 points and 12 rebounds for his career-high 13th double-double of the season. On March 20, he recorded 14 points and a then career-high 19 rebounds in a 132–120 overtime loss to the Dallas Mavericks.
In Game 3 of the Trail Blazers' 2016 first-round playoff series against the Los Angeles Clippers, Plumlee recorded career highs of 21 rebounds and nine assists in a 96–88 win. He became the first player with 19 or more rebounds and eight or more assists in a playoff game since LeBron James in 2010. He also became the first Blazer center with eight-plus assists in a postseason game since Arvydas Sabonis in 1999. In Game 4 of the series, Plumlee recorded 14 rebounds, 10 assists, three blocks and two points in a 98–84 win, tying the series at 2–2.
On December 7, 2016, in a loss to the Milwaukee Bucks, Plumlee became the fastest Portland player to tally 150 rebounds and 100 assists (23 games) since Scottie Pippen in 1999–2000 (22 games). On January 8, 2017, Plumlee recorded eight points, a career-high 12 assists, 10 rebounds, three blocks and one steal across 40 minutes in a 125–124 double-overtime loss to the Detroit Pistons. His 10 rebounds and 12 assists made him the first Blazers forward or center to have a double-double in those categories since Mychal Thompson in January 1984.
On February 13, 2017, Plumlee was traded, along with a 2018 second round draft pick and cash considerations, to the Denver Nuggets in exchange for Jusuf Nurkić and a 2017 protected first round pick.
Plumlee was a member of the United States national team that won the gold medal in the 2014 FIBA Basketball World Cup. He also won silver with the Under-18 team at the FIBA Americas Under-18 Championship in 2008.
Plumlee grew up with brothers Miles, who also played for Duke and currently plays for the Atlanta Hawks of the NBA, Marshall who also played for Duke and is also a professional basketball player in the NBA, and sister Madeleine who plays volleyball for the University of Notre Dame. He and Miles became the sixth pair of brothers to play at Duke at the same time. With Marshall's NCAA championship in 2015, all three Plumlee brothers won NCAA championships playing for Duke.
Plumlee's parents are Perky, a former Tennessee Tech basketball player, and Leslie (née Schultz), a former Purdue basketball player. The two met at a basketball camp during the summer of 1979. His grandfather Albert "Bud" Schultz played basketball at Michigan Tech (1944), his uncle William Schultz played basketball at Wisconsin-Eau Claire (1971–72), and his uncle Chad Schultz played basketball at Wisconsin-Oshkosh (1983–86).