Southampton have already begun the process of identifying Ronald Koeman's successor after the Dutchman joined Everton.
Koeman had long been linked with a switch to Goodison Park after it emerged that he was the Merseyside club's top target to replace Roberto Martinez, and the former Barcelona defender finally put pen to paper on a three-year deal on Tuesday.
The 53-year-old's departure represents a blow for Southampton after he steered them to seventh and sixth-place finishes in the Premier League in his two seasons at St Mary's Stadium.
However, Koeman's decision to leave has not caught the Saints unaware, and they are hopeful of finding a replacement capable of "taking the club to the next level".
A club statement read: "Southampton Football Club can today confirm it has accepted the resignation of first team manager Ronald Koeman, and completed negotiations with Everton over his move to Goodison Park.
"The search has already begun for the right appointment who can take the club to the next level and build on our track record of recent success, which culminated in a sixth-place finish in last season's Premier League, as well as qualification for the group stages of the Europa League.
"Our focus now is to build on our long-term plan, and work with a new management team who share both the club's and our supporters' values and ambitions."