He played college football for the Illinois Fighting Illini and was selected by the Pittsburgh Steelers in the first round of the 2008 NFL draft.

He won Super Bowl XLIII with the Steelers against the Arizona Cardinals, for whom he later played one season.

[14] He was expected to be a complement to Pro-Bowl running back Willie Parker,[15] in addition to returning kicks.

[14] Mendenhall fumbled twice in Pittsburgh's third pre-season game against Minnesota; they were attributed to adjusting to the faster pace of the NFL.

[17] Mendenhall fumbled once more in the Steelers final pre-season game,[18][19] but worked with running backs coach Kirby Wilson to fix the problem.

[21] Entering the fourth week of the 2008 season, Willie Parker suffered an injury which allowed Mendenhall to make his first NFL start.

[22] Mendenhall rushed for 30 yards on 9 carries,[23][24] but was forced to leave the game with a fractured shoulder in the third quarter after a hit by Baltimore Ravens linebacker Ray Lewis.

In 2010 Mendenhall ran for 1,273 yards and 13 touchdowns, helping lead the Steelers back to the Super Bowl against the Green Bay Packers, which they subsequently lost.

The loss was aided by a 4th quarter fumble by Mendenhall that led to a Packers scoring drive.

On January 1, 2012, Mendenhall left the last regular season game against the Cleveland Browns with a knee injury on the final play of the 1st quarter.

[30] Mendenhall signed a one-year contract worth up to $2.5 million with the Arizona Cardinals on March 13, 2013.

[36] Reacting to the death of Osama bin Laden and the American reaction to the death of Osama bin Laden on May 2, 2011, Mendenhall posted comments on his Twitter account criticizing the celebrations;[37] one tweet seemed to support 9/11 conspiracy theories.

Mendenhall later attempted to back pedal on his remarks, saying that Roethlisberger was "not racist" just like Brown is "not a dirtbag" and "Clearly it's no fun, when EVERYONE's the accused.