Goalkeeper Yann Sommer, centre-backs Francesco Acerbi and Stefan de Vrij, and right-back Matteo Darmian have all left the club.
Sommer, 37, joined Inter Milan in the summer of 2023 following a long Bundesliga career with Bayern Munich and Borussia Mönchengladbach.
In three seasons at the San Siro he made 139 competitive appearances, keeping 66 clean sheets, and won two Serie A titles, a Coppa Italia and a Supercoppa Italiana.
His starting place is expected to be taken by Spaniard Josep Martinez, who served as his understudy throughout his time at the club.
FC Basel and Club Brugge have been linked with the Swiss international as he considers his next move.
Acerbi, 38, arrived at Inter from Lazio in the summer of 2022, initially on loan before the deal was made permanent a year later.
He contributed five goals and five assists across 148 competitive appearances for the Nerazzurri.
Darmian, 36, joined Inter in 2020 and spent six seasons at the club, making 218 appearances across all competitions.
His trophy haul in Milan included three league titles, three domestic cups, three super cups and two appearances in the Champions League final.
De Vrij, 33, had the longest association of the four, arriving from Lazio as far back as 2018 and playing a central role in Inter's most successful period.
The Dutchman was part of the squads that reached the Champions League final in 2022-23 and 2024-25 and won two Serie A titles during his time in Milan.
Their departures mark the most significant defensive overhaul Inter have undertaken in years, with the club expected to bring in younger options as they reshape the squad for 2026-27.