Twice grand slam winner Wawrinka ended the rousing comeback effort by the Argentine at Flushing Meadows with a 7-6(5) 4-6 6-3 6-2 win to close out Day 10 at the year's last grand slam.
Del Potro, the 2009 winner, had missed nine successive slams due to a string of wrist surgeries before returning to Wimbledon, where he ousted Wawrinka in the second round and went on to claim silver at the Rio Olympics.
"It was an amazing match for me, one of my toughest matches, mentally and physically against Juan Martin," Wawrinka said in an on-court interview. "He's an incredible player and I'm really happy to have won that match."
A crowd favourite at Flushing Meadows since his five-set finals win over Roger Federer, del Potro charged to a 4-1 lead in the opening set before Wawrinka brought the set back on serve in the seventh game.
Del Potro's big forehand betrayed him in the tie-breaker, with three errors helping the Swiss claim the decider 7-5.
The Argentine had his right shoulder manipulated during a second-set changeover at 2-3 and he responded with a service break for a 4-3 lead and served out the set.
As the match wore on, it became evident that a lack of conditioning was wearing del Potro down and he became selective about which points to contest.
The fit Wawrinka charged to victory, finding the range with his stylish one-handed backhand for winners up the line.
As del Potro went out for the last game, the fans that had remained as the clock moved past 1:00 a.m. serenaded him and the big Argentine wiped away tears as "Ole, ole, ole, ole, Delpo, Delpo," rained down from the Arthur Ashe Stadium stands.
"Something difficult to describe with words," del Potro, who is ranked 142 and given a wild card into the event, told reporters about the salute.
"I can lose the match, but I will never forget this. It's bigger than a win in any match."
Wawrinka, the 2014 Australian Open winner and 2015 French Open champion, will next meet sixth seed Kei Nishikori of Japan, the 2014 Flushing Meadows runner-up, who upset world number two Andy Murray in five sets in their quarter-final.
Friday's other men's semi-final will pit world number one Novak Djokovic against French 10th seed Gael Monfils.
(Editing by Ian Ransom/Sudipto Ganguly)
