As a freshman at the University of Nebraska in 2009, Burkhead played in nine games, rushing for 346 yards on 81 carries with three touchdowns. As a sophomore in 2010, Burkhead was second on the depth chart behind senior Roy Helu. Burkhead played in all 14 games as the backup, and rushed for 951 yards on 172 carries and seven touchdowns. In 2011, Burkhead took over as the starting running back as a junior. Nebraska had little experience at running back that season, and Burkhead got the majority of the carries, including a school-record 38 carries against the Iowa Hawkeyes. He ended up rushing for 1,357 yards on 284 carries with 15 touchdowns and was named a first team All-Big Ten selection. In 2012, with expectations high, Burkhead sprained his knee in the season opener and missed two games before re-injuring the knee four games later. Burkhead missed six games total in the season, but still finished with five touchdowns and 675 yards on just 98 carries for a 6.9 yard average.

He graduated from Nebraska in three-and-a-half years with a bachelor’s degree in history. He earned repeated scholar-athlete awards throughout his career, including first-team CoSIDA Academic All-American in 2011 and 2012, and recognition as one of 15 National Football Foundation Scholar Athletes in 2012.

Burkhead is married to Danielle. Burkhead was the 2012 winner of the Uplifting Athletes Rare Disease Champion award. He was awarded for his work with a 6-year-old suffering from a rare pediatric brain tumor called a low-grade glioma. Burkhead’s commitment to community service has been personified by his friendship with that child, Jack Hoffman, a cancer patient from Atkinson, Nebraska. Jack contacted Nebraska in 2011, asking for a Burkhead photo. Burkhead offered to meet Jack, and his involvement in their relationship led to national notice when he arranged for Jack to suit up in a Cornhusker uniform and “run for a touchdown” in the 2013 Nebraska spring football game before a crowd of more than 60,000. President Barack Obama responded by inviting Jack and his family to the White House, and the family included Burkhead in its party. In honor of Jack Hoffman, Burkhead launched the Team Jack Foundation.

After being selected by the Cincinnati Bengals in the sixth round of the 2013 NFL Draft with the 190th overall pick, Burkhead signed with the team on May 13, 2013.

In 2014, Burkhead played in nine games for the Bengals, mainly on special teams. On offense, he had nine rushes for 27 yards and his first career touchdown (against the Cleveland Browns) and seven receptions for 49 yards. He had the most productive game of his career in the Bengals’ opening round playoff loss to the Indianapolis Colts, in which Burkhead started at wide receiver and totaled three receptions for 34 yards and one rush for 23 yards.

On March 14, 2017, Burkhead signed a one year contract with the New England Patriots worth up to $3.15 million.

On September 7, on Thursday Night Football, Burkhead made his debut as a member of the Patriots. He was in the starting lineup and had three rushes for 15 yards and one reception for eight yards in the 42–27 loss to the Kansas City Chiefs. On September 17, against the New Orleans Saints in Week 2, he recorded his first touchdown as a member of the Patriots when he hauled in a 19-yard pass from quarterback Tom Brady in the first quarter of the 36–20 victory. He finished the game with three receptions for 41 yards. On November 12, 2017 during Week 10 against the Denver Broncos, Burkhead had 10 rushes for 36 rushing yards, three receptions for 27 receiving yards and a receiving touchdown, and a blocked punt. He thus became the first player to both catch a touchdown pass and block a punt in the same NFL game since 1977. Burkhead finished his first season with the Patriots with 64 carries for 264 rushing yards and five rushing touchdowns and recorded 30 catches for 254 receiving yards and three receiving touchdowns. In the playoffs, the Patriots defeated the Tennessee Titans in the Divisional Round without Burkhead, but Burkhead returned for the AFC Championship Game where he recorded one carry for five yards in the 24–20 victory against the Jacksonville Jaguars to reach Super Bowl LII. The Patriots lost 41–33 to the Philadelphia Eagles. Burkhead recorded three carries for 18 yards and caught a pass for 46 yards in the Super Bowl.

On March 14, 2018, Burkhead signed a three-year contract extension with the Patriots. In Week 3 against the Detroit Lions, Burkhead suffered a neck injury and was placed on injured reserve on September 26, 2018. He was activated off injured reserve on November 26, 2018. The Patriots won the AFC East and earned the #2-seed for the AFC Playoffs.

On January 13, 2019 Burkhead scored his first-ever postseason touchdown in the Divisional Round with a six-yard run against the Los Angeles Chargers in a game New England won 41–28. One week later, he scored the game-winning touchdown in overtime as part of the 2019 AFC Championship game against the Kansas City Chiefs. The Patriots won the coin toss, which eventually set up the offense with a 1st & 10 at the Kansas City 15-yard line. Burkhead ran up the middle for 10 yards and another three yards on the next play setting up 1st & Goal. Burkhead ran again up the middle for a 2-yard touchdown, sending the Patriots to Super Bowl LIII. Before his overtime touchdown, Burkhead had previously scored a rushing touchdown with 39 seconds left to give the Patriots a 31–28 lead, though the Chiefs responded with a 39-yard field goal to force overtime. Burkhead finished the game with 12 carries for 41 yards and two rushing touchdowns and had the game’s longest run from scrimmage (14 yards). He also had four receptions for 28 yards.

In the 2019 season, Burkhead finished with 302 rushing yards and three rushing touchdowns to go along with 27 receptions for 279 receiving yards in 13 games.