The 34-year-old, who now plays for Royal Antwerp in Belgium, has been a mainstay in the Red Devils backline since making his debut in 2009.
Alderweireld has amassed the third-most caps in Belgium's history, making 127 appearances and scoring five goals.
He featured in the last five international tournaments for his country, which included three FIFA World Cups and two European championships.
The former Ajax Amsterdam defender is the latest member of Belgium's golden generation to quit internationals since the Qatar 2022 FIFA World Cup after Eden Hazard.
Belgium suffered a disappointing group-stage exit from the competition.
"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 counts Southampton, Atletico Madrid and Tottenham Hotspurs among his former clubs.
