The 38-year-old moved to St Mary’s from Swansea last summer and oversaw a top-flight return at the first attempt thanks to their Championship play-off final win against Leeds United.
But he has struggled since the Saint's promotion, with Sunday’s home humbling by Spurs the final straw for a side sat rock-bottom of the Premier League on five points after 16 matches.
A statement from the board of Southampton read: “We can confirm that we have taken the difficult decision to part ways with our Men’s First Team Manager, Russell Martin.
“Going into the start of the season, we all knew the challenges that we would face this year as we readjusted to life in the top flight, competing in the best and most competitive league in the world.
“However, the reality of our situation is clear. The board have supported Russell and his staff and been open and transparent regarding our expectations.
“We have all been on the same page in recognising the urgency of needing results to improve.
“We would like to take this opportunity to thank Russell and his staff for all the hard work and dedication they have given the club on and off the pitch over the last 18 months.
“Everyone connected with Southampton FC will always have fantastic memories of last season, especially the Play-Off Final win in May.”
Saints confirmed that Under-21s manager Simon Rusk will step up on an interim basis as they select a permanent replacement.
Martin had been rewarded with a new three-year contract in the summer after masterminding promotion but his focus on style over substance proved costly as Southampton repeatedly shot themselves in the foot.
Prior to his move down south, he had stints in charge of Wanderers' Buckinghamshire rivals Milton Keynes and Swansea City.
The statement continued: “Behind the scenes, we are encouraged by the continued development of talent coming through our academy.
“We are proud of the contributions our young players are making and are confident this will remain a source of strength and pride for everyone associated with the club.
“We are also deeply grateful for the continued support and positivity shown by our fans.
“We are witnessing first-hand the significant gap between the Championship and the Premier League, but your understanding and passion, even when results have not been what we all want, continue to drive our long-term commitment to the club.”
Martin began his playing career at Non League Lewes before joining Wycombe in 2004.
He played 142 times for the Chairboys, scoring five times.
During his time at Adams Park, he helped Wycombe reach two play-off campaigns in 2006 and 2008, as well as a League Cup semi-final in 2007.
After leaving Wanderers, Martin had spell as Peterborough United, Norwich City, Rangers and Milton Keynes.