Upshaw attended Eufaula High School, where he played for the Eufaula Tigers high school football team under head coach Dan Klages. In his junior season, Upshaw posted 96 tackles and three interceptions as he led Eufaula to a 14–1 season record, including the Tigers first state championship finale appearances since 1981. They lost 10–7 to Athens. As a senior Upshaw had 95 solo tackles, 65 assists, including 22 for loss and seven sacks to go with three fumble recoveries. He also had 20 receptions for 496 yards and three touchdowns as a tight end. He was the Alabama Class 5A Lineman of the Year by the Alabama Sports Writers Association and ASWA Class 5A All-State selection in 2007. Upshaw was ranked as the No. 4 defensive end in 2008 by ESPN.com.
After playing in all 13 games of his freshman season, Upshaw saw his playing time increase in his second season at Alabama. He made one start and appeared in all 14 games for the Crimson Tide in 2009. Upshaw made the most of his first career start against Kentucky, as he tallied four solo tackles, one sack and returned a fumble 45 yards for a key against the Wildcats. In the 2010 BCS National Championship Game Upshaw recovered a Garrett Gilbertfumble on an Eryk Anders quarterback sack with just 3:08 remaining in the game, that sealed the title for the Crimson Tide.
In his junior season Upshaw started 11-of-13 games for the Crimson Tide. He accounted for 52 total tackles, 14.5 tackles for loss, seven sacks, and four forced fumbles. In the 2011 Capital One Bowl against Michigan State, Upshaw led the defense for the Crimson Tide, who won 49–7, with a pair of sacks, five tackles, including three for a loss as well as forcing a fumble, and was voted the game's MVP for his effort.
On May 10, 2012, he signed a four year, $5,296,698 contract (with $3,587,000 guaranteed) with the Ravens. During the regular season, he was noted for his solid play against the run. He also recorded 1.5 sacks. In Super Bowl XLVII, Upshaw recorded his first forced fumble against San Francisco 49ers running back LaMichael James, which the Ravens recovered and scored on the ensuing possession.