Vegard Forren has returned to former club Molde just six months after joining Southampton, while Richard Chaplow has had his deal terminated.
The 25-year-old defender arrived at St Mary's for a reported £3.5million in January, amidst reported interest from Liverpool and Everton.
However, Forren failed to impress manager Mauricio Pochettino and did not make a single first-team appearance last season.
It has seen Southampton cash in on Forren at the earliest opportunity.
The Norway international returns to Ole Gunnar Solskjaer-managed Molde for an undisclosed fee, understood to be near the amount Saints forked out for his services in January.
Another leaving Southampton on Thursday is long-serving midfielder Chaplow.
A part of the side that secured back-to-back promotions from League One to the top flight, the 28-year-old's contract has been mutually terminated allowing him to move to Millwall.
Saints confirmed the two departures on their website, adding: "Southampton football club would like to wish Richard and Vegard the very best in their future careers."
The duo are unlikely to be the last to leave the club this summer.
Billy Sharp, Dean Hammond and Tadanari Lee are among players told they can leave by manager Pochettino, as are Lee Barnard and Steve de Ridder.
Saints have so far only brought in Lyon defender Dejan Lovren, although a move for Celtic's Victor Wanyama is understood to be close to completion.