Doug Wilson has been general manager of the Sharks for 19 seasons.
Joe Will is the interim general manager until a full-time replacement can be found. Will has been running the hockey operations since Wilson went on medical leave.
Wilson said in a statement that he was stepping down from his current duties to focus on his health and recovery.
Hasso Plattner said there will be a search for the next general manager. Jonathan Becher and Will will be in charge of the search.
San Jose made the playoffs 14 times under Wilson and reached the Stanley Cup Final. The Sharks won more regular-season games than any other team.
Doug and his staff produced remarkable results over a span that few NHL teams can match.
Wilson played for the Sharks in their first season. The hockey Hall of Fame inducted the player who won the NHL's most prestigious award, the Norris Trophy, last year.