Wilder led the Blades to two promotions to reach the Premier League and a ninth-placed finish in their first season back in the top-flight for 14 years last year.
However, United seem destined for a return to the Championship as they sit bottom of the table, 12 points adrift of safety with just 10 games left to play.
"Sheffield United confirms that Chris Wilder has left the Club by mutual consent," the club said in a statement. "The Board and Chris Wilder, who has managed the Blades to more than 100 wins in his almost five years at Bramall Lane, made the decision following discussions."