On a day when rain caused a four-hour delay on the outside courts, forcing organisers to consider playing on the middle Sunday for the first time since 2004, the giant Del Potro shone beneath the Centre Court roof.
His 3-6, 6-3, 7-6 (7/2), 6-3 second round victory over Wawrinka brought back memories of his stunning US Open win in 2009 before a series of wrist injuries pushed him to the brink of retirement.
The world number 165 from Argentina, who was a semi-finalist in 2013 in what was his last appearance at Wimbledon, next faces either French 32nd seed Lucas Pouille or Donald Young of the United States. Del Potro is playing in his first major since the Australian Open in 2014 after undergoing three wrist surgeries.
"It feels amazing, it's a great sensation," said the 27-year-old. "I enjoyed the crowd. It's an incredible feeling, that's why my hands are still shaking. "I feel alive again. After sitting at home for two years, this feels like a second or third career," added the former world number four.
Wawrinka, a quarter-finalist in 2014 and 2015, fired 47 winners past Del Potro but was undone by 48 unforced errors. Meanwhile, Wimbledon suffered a third day of rain delays. Only one minute of action was possible on the outside courts in the first four hours while most players didn't get beyond warming up.
The tournament already had a backlog of 16 second round ties and with more rain expected Saturday, organisers admitted that play may take place on Sunday for the first time since 2004 and only the third time overall.
"Sunday play is being considered but a decision won't be made until tomorrow," a spokesman told AFP. All men's second round doubles matches were reduced to best of three sets rather than five.
Novak Djokovic and Roger Federer can take a step closer to a Wimbledon semi-final duel when they battle for places in the last-16 later Friday.
Defending champion and top seed Djokovic, bidding for a third successive Wimbledon title and fourth in total, takes on America's Sam Querrey. Victory will give the Serb a 31st successive Grand Slam win taking him level with Rod Laver on the all-time list, six behind the record set by Don Budge in 1938.
Djokovic has an 8-1 career record over the 28-year-old Querrey who has only reached the fourth round on one occasion, back in 2010.
Third seed Federer, the seven-time champion, saw off world number 772 Marcus Willis in the second round and Friday faces another British player, 91st-ranked Daniel Evans.
Federer is looking to clinch his 150th win on grass courts. Evans, 28, hopes to become the first British man other than Andy Murray to reach the round of 16 at a Grand Slam since Tim Henman made the semi-finals at the 2004 US Open.
Defending women's champion Serena Williams, chasing a seventh Wimbledon title and Open era record-equalling 22nd major, faces fellow American Christina McHale on Centre Court.
Williams has a 2-0 head-to-head advantage over McHale, the world number 65, with both wins coming this year.
Sister Venus, a five-time champion and the oldest woman in the draw at 36, is on Court One facing Russia's Daria Kasatkina.
Also bidding for third round spots on Friday are Australian 15th seed Nick Kyrgios who faces Dustin Brown of Germany in a clash between two men who have both defeated Rafael Nadal at Wimbledon in recent years.
Japanese fifth seed Kei Nishikori meets Russia's Andrey Kuznetsov, while two-time women's champion Petra Kvitova takes on Ekaterina Makarova of Russia.