After playing college football for the Boise State Broncos, he was signed by the Philadelphia Eagles as an undrafted free agent in 2003.

On defense, Mikell replaced the injured Sean Considine as the starting strong safety in 2007 and remained in that role through 2010.

The play helped the Eagles preserve a 7–6 lead at halftime, and Philadelphia went on to win, 27–6, to clinch their fourth consecutive NFC East title.

Mikell was a backup safety behind Pro Bowlers Michael Lewis and Brian Dawkins for the 2004 NFC Championship team and played in Super Bowl XXXIX.

His most significant contribution on special teams came on October 23, 2005, when, with the Eagles trailing the San Diego Chargers, 17–13, late in the fourth quarter, he blocked a field goal attempt by placekicker Nate Kaeding (who to that point had not missed a field goal all season), which teammate Matt Ware returned 65 yards for a touchdown to secure a 20–17 win.

In a Christmas Day win at Dallas in 2006, Mikell propelled the Eagles with a key tackle for loss of running back Marion Barber on fourth down to finish off a goal-line stand.