The Russian, ranked 46 places below the world number three, bamboozled the US Open champion with a combination of powerful serves, heavy ground strokes and a delicate touch at the net, displaying a killer instinct that belied his tender years and apparently fragile frame.
Fifth seed Wawrinka was troubled throughout by a knee problem, which he iced regularly at the change of ends, but the manner of the 2014 Australian Open and 2015 French Open champion's first-round departure was nevertheless surprising.
Having backed up impressive form on grass on the biggest stage, Medvedev's reward for slaying a giant on his debut at the All England Club - this was the 21-year-old's first victory in the main draw of a grand slam - is a second-round match against German veteran Tommy Haas or Belgium's Ruben Bemelmans.
It marks another disappointingly early exit at SW19 for Wawrinka, who lost in the second round to a resurgent Juan Martin del Potro last year and has never advanced beyond the quarter-finals of the grass-court slam.
Sloppy serving in the fifth game of the opening set, and some bad luck when a net cord went against him, saw Wawrinka fall behind.
He had to save two break points in his next service game, but Wawrinka was unable to reel Medvedev back in, the Russian's big serve and deceptively powerful forehand proving too much for this year's French Open finalist.
It was Medvedev, though, who gave up his serve first in the second set, Wawrinka seizing on a second serve to unleash a determined, jumping forehand winner.
And although the Swiss suffered a break in the seventh game, Medvedev gave it straight back when he succumbed to a trademark one-handed backhand down the line. Despite taking the set, Wawrinka remained uncomfortable and received immediate treatment to his knee.
There was a step-up in quality in the third set, Medvedev winning the rally of the match by digging out a drop shot and then showing quick reflexes to execute a brilliant volley right at the net.
He was rewarded by earning the only break and sealing the set to move back in front when Wawrinka fired successive backhand service returns wide.
The knee problem perhaps taking its toll, Wawrinka became increasingly despondent as the fourth set slipped away from him, Medvedev earning a decisive break with a piercing backhand down the line, and the Russian broke again before sealing it on serve with his third match point.