First-team assistant coach Richard Kitzbichler has also left St Mary's, the club have confirmed.
A Southampton statement read: "Southampton Football Club can confirm it has parted company with men's first-team manager Ralph Hasenhuttl.
"Hasenhuttl, who was appointed in December 2018, departs having made a significant contribution to the club, overseeing some memorable results and also playing a key role in the development of our club infrastructure, identity and playing squad.
"However, we now believe it is an appropriate time to make a change. Everyone involved with the club would like to express their sincere thanks to Ralph for all of his efforts, as well as the unwavering commitment he has shown throughout his time as manager.
"First-team lead coach Ruben Selles will take charge of the side on an interim basis for our game (against Sheffield Wednesday) on Wednesday night. The club will be announcing a permanent replacement in due course."