Gaston Ramirez will leave Southampton following the expiration of his contract, while goalkeeper Kelvin Davis is to be offered a "behind-the-scenes" role.
Uruguay international Ramirez arrived at St Mary's Stadium from Bologna for a club-record fee in 2012, but has failed to live up to his billing since making the switch.
Loan spells at Hull City and Middlesbrough over the past two seasons have not convinced Southampton to retain Ramirez, who will now be looking for a new club after scoring eight goals in 55 appearances for Southampton.
Davis, meanwhile, could extend his 10-year stay on the south coast, albeit not as a player.
"Kelvin's tremendous passion and commitment to the club are two of the reasons why we are currently in conversations with him about a new role moving forward, in which he can continue to help the club's progression," said executive director of football Les Reed.
Young goalkeeper Will Britt will also leave the club.