The Queenslander took advantage of one of the former world No.1's Jekyll and Hyde days on Monday, "hanging tough" in the final set to come from behind and win 6-2 1-6 6-1 1-6 6-4 in three hours 22 minutes on Court Suzanne Lenglen.
But hopes of an all-Australian second-round clash evaporated with Alexei Popyrin cutting a dejected figure after capitulating in four sets to American Zachary Svajda following a hot start.
"It's huge," declared Walton, after clutching his head in his hands in near disbelief at repeating his previous career-best triumph over Medvedev at the Cincinnati Open last August, but on a grander stage.
"That win in Cincinnati definitely gave me the belief. I hung tough, I believed and I'm really excited. To get a first top-10 win at a slam is pretty epic."
Walton reckoned that after four curiously uneven stanzas, he was "proud" of how he'd rallied in the fifth set from 3-1 down when not knowing "which version" of Medvedev was going to materialise.
The world No.97 felt the key was saving two break points with the Russian on the verge of going 4-1 up. "I knew I just had to fight," he shrugged.
Fight he did. At 4-2 down, Walton won the next two games, then survived three break points at 5-5 before the Russian cracked, throwing in a double fault to give the Aussie match point and then blasting a drive volley long to be broken to love.
Walton reckoned the 32C temperatures certainly helped. "We grew up in the heat," he said on court. "I really like it when it's hot in Paris."
Medvedev didn't look as though he did, even if he suggested the heat had nothing to do with his loss.
Still, he had begun the match like a bear with a sore head, grumpy about everything and leaving Walton to be amazed to effectively be gifted two breaks.
His wife, the normally quiet Daria, in the players' box, quickly scolded Medvedev: "It's hot for everybody. Everybody is suffering. You need to behave!"
He did - and in set two, pinned the Aussie back on the baseline relentlessly, only for Dr Jekyll to reappear in the third when his poor choice of drop shots saw Walton pounce mercilessly.
Walton still nagged away, even when the match looked on Medvedev's racquet following the Russian's superb fourth set, and hoped his win would be big news back in his little rural hometown of Home Hill.
"I think it will probably be in the newspaper tomorrow morning," he beamed.
"It's great, just a pretty cool story to have been brought up in Home Hill and then moved to Brisbane, then moved to America (as a college player), and now playing pro. It's a pretty special story."
Earlier, Popyrin, who was left tearful after losing in five sets in the first round at the Australian Open in January, was left numb after his 3-6 6-3 7-6 (7-3) 7-5 loss to Svajda.
Like Medvedev, some ill-judged drop shots eventually cost him dear just when it had seemed he was about to level at two sets all when serving for the fourth set at 5-3.
"I don't know yet what's next, I'm not sure, it's too close to the match," sighed the disconsolate Popyrin, who thought he'd rediscovered his mojo and turned a corner at the Italian Open after a difficult campaign.
