James left Indianapolis as its all-time leading rusher with 9,226 yards. After James departure in March 2006, the Colts won Super Bowl XLI the following season. Although he was not on the team at the time, Colts owner Jim Irsay still sent him a Super Bowl ring.

James signed a four-year, $30 million deal with the Arizona Cardinals on March 23, 2006. With the retirement of Corey Dillon, James became the active leader in career rushing yards at the start of 2007, and remained so through his last game in November 2009 (though he would be passed by LaDainian Tomlinson by the end of the season). James went through a stretch of 10 games out of the 2008 season where he carried the ball only 20 times. Through this time, Ken Whisenhunt brought him in strictly as a pass protector. In Week 17 against the Seattle Seahawks, James carried the ball 14 times for 100 yards. James said he would not come back to Arizona following the 2009 NFL playoffs, despite a year left on his contract. In the Cardinals’ first playoff game since 1998, James averaged 4.7 yards per carry and ran for 100 yards. In the Divisional Round of the playoffs, James rushed for 57 yards and a touchdown in the Cardinals’ upset victory over the heavily favored Carolina Panthers. James rushed for 73 yards in the Cardinals’ 32-25 win over the Philadelphia Eagles in the NFC Championship game. James rushed 9 times for 33 yards in the Cardinals’ 27-23 loss to the Pittsburgh Steelers in Super Bowl XLIII.

Edgerrin was inducted into the University of Miami Sports Hall of Fame on April 23, 2009 at its 41st Annual Induction Banquet at Jungle Island in Miami.

His long-time girlfriend, the mother of his children, died of cancer in April 2009. After this, he asked for his release from the team, and the Cardinals honored his request on April 28.

After spending the 2009 offseason grieving with his four children and declining NFL offers, James finally agreed to a one-year, $2 million contract with the Seattle Seahawks on August 24, 2009, missing the team’s training camp. The team released running back T. J. Duckett to make room for James on the roster. However, James rushed for only 125 yards on a career-low 46 carries. He played in only seven games, and on November 3, 2009, Seattle cut him from the team.

James currently resides in Miami, Florida. He has six children. On April 14, 2009, Andia Wilson, James’ long-time girlfriend and the mother of four of his children, died from leukemia at the age of 30. He is the second cousin of current LA Chargers safety, Derwin James.

On July 26, 2011, James announced his retirement from professional football. He had amassed 12,246 rushing yards (11th all-time at the time of his last game in 2009) and 80 rushing touchdowns (15th).

On September 23, 2012, James was inducted into the Indianapolis Colts Ring of Honor during the week 3 game against the Jacksonville Jaguars.