He played college football for the Midwestern State Mustangs and was signed by the Indianapolis Colts as an undrafted free agent in 2001.

Rhodes played two years at Tyler Junior College, where he earned All-American honors and twice was named an all-conference selection.

In that game, the Indianapolis Colts' starting running back, Edgerrin James, injured his knee and ended his season.

That year, Rhodes ran for the most rushing yards by an undrafted rookie in NFL history, with 1,104, despite only starting the final nine games of the season.

During the 2006 NFL season, Rhodes split time with rookie running back Joseph Addai, as James left for the Arizona Cardinals.

On February 4, 2007, in Super Bowl XLI, he scored a one-yard touchdown and rushed for over 100 yards to help the Colts claim a 29–17 victory.

During the 2008–09 season, Rhodes split time with Joseph Addai and ran for 538 yards and a team-leading six rushing touchdowns.

Rhodes and the Tuskers qualified for the 2010 UFL Championship Game, but were ultimately defeated by the defending champions Las Vegas Locomotives 23–20.

On December 7, 2010, just 10 days removed from the UFL Championship game, the Indianapolis Colts announced that they had signed Dominic Rhodes for the remainder of the 2010 season as well as the playoffs.

Less than a week before the 2011 regular season began, NFL Commissioner Roger Goodell announced he was suspending nine different free agents, one of whom was Rhodes.

[6][7] In a week 4 win over the Sacramento Mountain Lions, Rhodes ran for 217 yards and three touchdowns, both UFL single game records.