Jeffires spent his first nine seasons (1987–95) in the NFL with the Oilers, where he was selected to three consecutive Pro Bowls from 1991 to 1993. In 1991, Jeffires led the league in receptions and was a First-team All-Pro. He then spent the 1996 season with the New Orleans Saints.
As of 2008[update], Jeffires is coaching the Bay Area Gamblers, a semipro football team in Pearland, Texas. Though his last name is spelled Jeffires, it is pronounced Jeffries, a fact that commentators often noted during broadcasts of games in which Jeffires was playing. The 1991 Nintendo Entertainment System console game, Tecmo Super Bowl, incorrectly listed Jeffires' name as "Jeffries".
Jeffires currently resides in suburban Houston with his wife, Robin, and their two children, Andrea and Haywood III. Jeffires remains beloved and active in the Houston community, devoting countless hours assisting special needs children, and is frequently tapped for personal appearances and interviews.