The 34-year-old, who played 127 times for his country in a career spanning 13 years, is the third most-capped player in Red Devils history.
Former Tottenham and Atletico Madrid centre-back Alderweireld represented Belgium at five consecutive major tournaments, including three World Cups and two European Championships, and was a member of the squad that finished third at Russia 2018.
But following a disappointing group stage exit in Qatar last year, he has now become the latest experienced member of their squad to call time on his international career.
"As a little boy, I dreamed of playing for the national team," Alderweireld told the Belgium national team's official website. "I am very grateful and proud that this dream has become a reality.
"I can look back, 14 years later, on 127 international matches, three World Cups, two European Championships and countless beautiful memories.
"With pain in my heart, I announce that I will retire from the Red Devils with immediate effect I have given myself completely, physically and mentally.
"I want to thank all my team-mates and the staff for the unforgettable moments we shared together. Without them, none of this would have been possible."
Alderweireld made his debut in 2009 during a 1-1 draw with Chile, though he did not become a regular until 2013.
He subsequently was a member of their squad at the Brazil 2014, Russia 2018 and Qatar 2022 World Cups, as well as Euro 2016 and Euro 2020.
His retirement follows team-mate Eden Hazard's decision to bow out following their disappointing Qatar campaign.
Belgium will play their first games under new coach Domenico Tedesco later this month, with a Euro 2024 qualifier against Sweden and a friendly against Germany.
A General Assembly met virtually on Friday and clubs ratified last month's decision from organisers to end the 2019-20 season, which has been halted since March amid the coronavirus pandemic.
All 16 teams in the top-flight had played 29 regular-season matches before the campaign was stopped, with Brugge 15 points clear of Gent at the top of the table.
The league season has now been declared over and no play-offs will be played to determine final positions, as is usually the case in Belgium's top division.
It is Brugge's third title in the past five seasons and they will directly enter the group stage of next season's Champions League.
Gent go into the third qualifying round of Europe's premier club competition by virtue of being one point clear of third-placed Sporting Charleroi when the league was halted.
Despite the league being brought to an end, the general assembly concluded they would "try to play" the Belgian Cup final "during the last weekend authorised by UEFA and before the start of the regular competition for the 2020-21 Pro League season".
Antwerp are fourth in the league but will gain automatic entry to the Europa League instead of Charleroi if they are able to play, and win, the final against Brugge.
If Brugge triumph in the final or the match cannot be held, Antwerp will instead have to go through Europa League qualifying along with fifth-placed Standard Liege, with Charleroi going straight into the group phase.
Waasland-Beveren are relegated, as they sat two points adrift of KV Oostende in the standings.
The health scare was revealed by the Belgian club on Friday, with former Arsenal, Ajax and Barcelona winger Overmars under orders to "take it easy".
Antwerp posted on their social media accounts: "Marc Overmars, director of football affairs at RAFC, became unwell last night and was admitted to hospital with a mild stroke. Marc is doing well in the meantime, but will have to take it easy for a while.
"Marc and his family are focusing on his recovery and do not wish to comment further. RAFC wishes Marc a speedy recovery!"
Antwerp hired Overmars in March, little over a month after he left Ajax after sending inappropriate messages to female colleagues.
Overmars sent messages and photographs to several women who worked at the Dutch club – behaviour he admitted was "unacceptable".
Ajax replied to Antwerp's announcement of Overmars' hospitalisation by posting: "Wishing you strength and strength with your recovery, Marc."
Overmars, 49, scored 17 goals in 86 games for the Netherlands in an international career that ran from February 1993 through to the 2004 European Championship.
