The 33-year-old was tasked with taking the Saints back to the Premier League after their relegation last season, but he only managed two league wins in his time at St Mary's, which saw his position become untenable.
In a statement, technical director Johannes Spors said: “Will is a great person who gave everything to try and improve performances and results.
"Ultimately, that process has taken longer than any of us would have liked. By making a change now, we believe it gives us the best chance of turning things around this season and climbing back up the league table."
Still, who became the youngest manager in Championship history at the start of his tenure, had success in France with Reims and Lens before moving to the UK.
His coaching staff have also departed.
The Saints' under-21 manager, Tonda Eckert, will take charge temporarily as they look for a successor.
Rumours have begun already, with former managers Ralph Hassenhutl and Russell Martin both linked to the role.
Sinking ship
It was a tough time for Still at Saints, but it had started well, as they came from behind to beat Wrexham on the opening day of the season.
However, underperforming their xG and countless defensive mishaps cost the team dearly over the next 12 games.
Six draws and five losses followed, including the final nail in the coffin on Saturday - a 2-0 defeat to Preston North End.
The support at home had become toxic in recent weeks, with chants of 'you don't know what you're doing' towards the dugout whilst some of the fans' ire was directed at the club's owners Sport Republic.
After the weekend loss, Still said: “I understand their (supporters') frustration and how angry they are with me, the players, the board. I know how important their football club is to them. When they get behind us it’s amazing, but we need to do enough for that to happen.”
Still will have no more time to turn it around, and Southampton now have a mountain to climb if they are to fight anywhere near the promotion spots this season.