Witsel earned 130 caps and was part of the team which finished third at the 2018 World Cup in Russia. He started all three games at the 2022 World Cup in Qatar, where Belgium failed to progress from their group.
"After careful consideration, it was with great emotion that I made the decision to retire from international football," the Atletico Madrid player wrote on Instagram on Friday.
"It has been a great pride to represent my country for the past 15 years. Now it is important for me to devote more time to my family and to focus on my club."
Witsel made his senior debut in March 2008 in a 4-1 friendly loss to Morocco, scoring his first goal for Belgium.
At club level he played for Standard Liege, Benfica, Zenit Saint Petersburg, Tianjin Quanjian and Borussia Dortmund before joining Atletico in July last year.
Witsel's announcement that he was leaving the international side follows similar decisions by defender Toby Alderweireld, in March, and former captain Eden Hazard in December.
