The caveat is that Wawrinka was clearly struggling with a troublesome knee, which required a substantial period of icing after the second set, but the injury will not hide the severity of this loss, this opening day defeat no one had expected.
Wawrinka's name will garner the headlines, but for all his despair there was joy for young Medvedev, the 21-year-old Russian who sits at No49 in the world rankings and had never before been past the first round of a grand slam.
Medvedev, who swelled with confidence as Wawrinka slunk into a shell of his normal barnstorming self, struck more aces and more winners than the Swiss, and at the close was so pumped full of bravado that he was dishing out drop shots and lobs like it was a training session near his Monaco home.
He only moved into the world's top 50 for the first time on Monday.
On this evidence he should make himself comfortable.
"I have no words to describe this," he said.
"I guess this memory will be with me for ever."
Having reached the final of the French Open less than a month ago, this has been far from the grass court season Wawrinka was hoping for as he dreamed of becoming only the ninth man to win the career slam of all four majors.
He was dismissed from Queen's in the first round by Feliciano Lopez, sat through a bristly pre-Wimbledon press conference in which he complained he was sick of being asked questions about Roger Federer, and now finds himself on the receiving end of the opening day's standout result.
No wonder he described it as a "tough, tough day".
His knee problem is nothing new - he had similar troubles in Australia earlier this season - but it has been exacerbated by the grass.
"I had some problem with the knee with Queen's, so that was not the way I wanted to get ready for this tournament," Wawrinka said.
In contrast to Wawrinka's woes on the turf, Medvedev battled his way to the quarter-finals at Queen's, before reaching the semifinals at Eastbourne.
"I've had a great grass court season so far," he said.
"I was feeling confident. I think my game suits really well on grass, because I don't have a huge serve but it's quite strong and very precise.
"Then I have a really flat game, which no one likes to play. I am good at the key moments."
Medvedev had taken the first set 6-4 but looked like his race may have been run when Wawrinka snapped back to claim the second.
That knee started to take its toll, though, and soon the lanky Medvedev was back in the driving seat, before eventually sealing the match in four sets.