After two years at Midwestern State University, Rhodes decided to go the NFL. Despite his college experience, he was not chosen in the 2001 NFL Draft. He was signed as an undrafted free agent by the Indianapolis Colts. In a 2001 game against the Kansas City Chiefs, Rhodes returned a kickoff for a touchdown. In that game, the Indianapolis Colts' starting running back, Edgerrin James, injured his knee and ended his season. As a result, Rhodes was the starting running back for the rest of the Colts' 2001 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. Rhodes missed the entire 2002 season due to a torn ACL. After recovering, he backed up James from 2003–2005. During the 2006 NFL season, Rhodes split time with rookie running back Joseph Addai, as James left for the Arizona Cardinals. Rhodes finished the year with 641 yards and five touchdowns. 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.
Oakland Raiders
Rhodes became a free agent for the 2007 free agency period. On March 9, he signed a two-year, $7.5 million contract with the Oakland Raiders. On July 3 he was suspended for four games for violating the NFL's substance abuse policy. Rhodes was released by the Raiders on April 28, two days after they drafted running back Darren McFadden fourth overall in the 2008 NFL Draft.
Indianapolis Colts (second stint)
On May 7, 2008, Rhodes returned to the Colts on a one-year, $605,000 contract. During the 2008-09 season, Rhodes split time with Joseph Addai and ran for 538 yards and a team-leading six rushing touchdowns. He contributed in the passing game as well, recording 302 yards and three TDs receiving. During the offseason, on April 19, 2009, Rhodes signed with the Buffalo Bills on a two-year deal. The Bills ended up releasing Rhodes during the preseason, without him playing a single down for them.
Florida Tuskers
Rhodes was signed by the UFL's Florida Tuskers for their 2010 season. During the 2010 season, Rhodes set UFL single-season records for total touchdowns, rushing yards and all-purpose yards. He was also third in the UFL in yards from scrimmage and second in kickoff return average. Rhodes scored at least one touchdown in each of the first seven games of the eight game season. Rhodes and the Tuskers qualified for the 2010 UFL Championship Game, but were ultimately defeated by the defending champions Las Vegas Locomotives 23-20.
Indianapolis Colts (third stint)
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. Rhodes played in their remaining three games that year, and finished the season with 37 carries for 172 yards and no touchdowns. He also played in their playoff loss to the New York Jets. Following the Colts playoff loss, Rhodes became a free agent. During the offseason, NFL Commissioner Roger Goodell announced he was suspending nine different free agents, one of which was Rhodes. The suspension was to be for at least an entire year and likely a result of failing a third drug test. Since Rhodes was soon-to-be 33 years old, it was widely believed no team would sign him to wait a year before he could play for them, and it likely signaled the end of his NFL career.
Virginia Destroyers
The Virginia Destroyers announced on September 8 that they had re-signed Dominic Rhodes for the 2011 season, their inaugural season in Virginia. In a week 4 win over the Sacramento Mountain Lions, Rhodes ran for 217 yards and three touchdowns, both UFL single game records. Rhodes would be named the UFL's offensive player of the year for 2011. After going 4-1 in the shortened season, Rhodes and the Destroyers defeated the two-time defending UFL Champion Las Vegas Locos 17-3 in the 2011 UFL Championship Game in front of a jam-packed crowd at the Virginia Beach Sportsplex. Rhodes ran for 90 yards and a touchdown in the game. Rhodes is actually one of four former NFL players to win a Super Bowl and a UFL Championship. Rhodes' teammates on the 2011 Virginia Destroyers included LB Diyral Briggs, DT Jay Alford and WR John Standeford who all share the same claim.
On March 27, 2013, at age 34, Rhodes signed with the Montreal Alouettes of the Canadian Football League. He was released on June 16, 2013. NFL rushing statistics
