"After careful consideration, it is with great emotion that I have taken the decision to retire from international football," the 34-year-old Atletico Madrid player announced on social media.
Witsel follows fellow thirtysomethings Eden Hazard, Toby Alderweireld and the number two goalkeeper Simon Mignolet in deciding to hang up the national shirt.
Only Jan Vertonghen, with 147 caps, has played more games for Belgium than Witsel.
In March, the defensive midfielder was omitted by new coach Domenico Tedesco from the squad to face Sweden,in the first game of the Euro-2024 qualifiers.
Tedesco showed his intention to rejuvenate the squad by discarding ten of the 26 players from the squad that was eliminated in the group phase at the 2022 World Cup in Qatar.