Brenly was replaced by third base coach Al Pedrique, who will take over for the rest of the season. Pitching coach Chuck Kniffin also was fired and bench coach Robin Yount quit.
Former Cy Young winner Mark Davis moved from bullpen coach to pitching coach, Glenn Sherlock switched from first base coach to third base coach, director of player development Tommy Jones became first base coach and Lorenzo Buddy replaced Yount.
Brenly took the fall for a team off to a 28-50 start, one helped along by a host of injuries and the trade of pitching star Curt Schilling.
"The blame does not soley fall on Bob's shoulders, as we have failed in many facets on the field and in the clubhouse," Diamondbacks CEO Jerry Colangelo said. "However, with disappointments come change."
Brenly took over in 2001 and guided the Diamondbacks to their first World Series title as a rookie manager. He also won the NL West in 2002.