The Saints returned to the second tier of English football for the first time in 11 years after a difficult season that saw them go through three different managers.
Semmens had been Southampton CEO since 2019, having previously been part of the club's board of directors.
A statement from the club read: “We would like to thank Martin for his hard work and dedication and wish him the best for the future.”
“These are the first of many changes that we will be making to ensure the success of the club.
“Our incoming director of football, Jason Wilcox, will lead a review of the football department and we will announce the club’s leadership team for next season in the coming weeks.
“By taking these steps now, we are laying the groundwork for our goal of returning Southampton FC to the Premier League as soon as possible.”
Southampton are on a 12-game winless run in the Premier League.