The 37-year-old made his 140th and last appearance for the national side in their 2-1 World Cup quarter-final loss to eventual champions Spain in July.
“It’s time to make way for the youngsters and the new generation,” Witsel said in a social media post.
“I never imagined achieving so much when I started out at just 18 years old.”
Witsel made his debut in 2008 and became a key player for Belgium’s ‘golden generation’, which also included Kevin De Bruyne, Romelu Lukaku and Eden Hazard.
They never managed to win a major tournament, coming closest at the 2018 World Cup when they lost to France in the semi-finals.
Only long-time teammate Jan Vertonghen, with 157 caps, has played more times for Belgium than Witsel.
He joined Ligue 1 club Nice in the close-season from Girona, having previously played for Borussia Dortmund and Atletico Madrid.