That latest setback left Saints languishing just one place and one point above the relegation zone.
In a change from recent appointments, and with eight games remaining to ensure they are not relegated, Southampton are working to a different criteria than in the recent appointments of Mauricio Pochettino, Ronald Koeman, Claude Puel and Manuel Pellegrino.
Assistant manager Carlos Compagnucci and assistant first-team coach Xavier Tamarit have also left the club.
"The club will look to appoint a new management team as soon as possible, with the search for a replacement already underway".
Mark Hughes is the leading candidate for the vacant managerial position after Southampton prioritised the need for Premier League experience and an immediate ability to galvanise their flagging squad.
Now, it's claimed that Southampton are turning their attention to Celtic boss Rodgers, and may hope to lure him back to the Premier League after almost two years in Scotland.
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To rub salt in the wounds Puel is now flourishing at Leicester, who currently lie eighth.
Croat Bilic was dismissed by West Ham last November after more than two years in charge at the East London club, during which he led them to seventh and 11th place finishes in the Premier League.
Saints chief Reed sees his brand of attacking football, ability to improve players - like Rodgers dramatically has at Celtic since May 2016 - and tactical nous as being perfectly suited for the St Mary's Stadium.
They are in the FA Cup quarter-finals but have five away games out of their last eight in the league.
The Times says that top of Southampton's wishlist to succeed Pellegrino is Marco Silva, the former Watford and Hull City head coach, but he is in advanced talks with Benfica over a two-year deal.