Liebherr takes over as interim as manager Pochettino’s future is also in doubt.
Nicola Cortese has resigned as non-executive chairman of Southampton, the Premier League club have announced.
Saints said club owner Katharina Liebherr would take over Cortese’s post while the club looked to appoint a chief executive.
“With great regret we have accepted the resignation of Mr Cortese,” Liebherr said in a statement.
“He has done a wonderful job at the club and we very much wanted him to stay. A search has now begun for a successor,” she added.
“In the meantime, it is business as usual and we will ensure that the manager, the team and all the staff at the club have all the help and support they need.”
Cortese joined Southampton in 2009 after playing a key role in the purchase of the south coast club by Swiss businessman Markus Liebherr – Katharina’s father.
The Italian oversaw the Saints’ rise from League One to the Premier League but his exit came amid reports of a disagreement with Katharina Liebherr, who became the club’s owner after her father’s death in 2010.
Cortese’s shock departure leaves a big question mark over the future of manager Mauricio Pochettino, who has overseen the club’s improvement this season.
Last May, Pochettino said he would leave St Mary’s if Cortese departed.
“I would not understand staying in this role if Nicola was not here,” Pochettino said at the time.
“The person that actually called me from the start, told me about the project and put their faith in me was Nicola.
“I have great respect as well for Southampton, the club and the supporters, but Nicola has been the one that has placed his trust and faith in me.
“I wouldn’t see myself in this club if it was not for him. I think I am a very transparent person, a very honest person.”
Cortese stunned many within English football by sacking Saints manager Nigel Adkins, who guided the club to back-to-back promotions, in January last year and bringing in Pochettino, who had no track record in English football
The Argentinian led Saints to a 14th-placed finish last season and they are currently ninth in the table.