Zverev was two points from a win after going up 5-4 in the fourth set tiebreak before crashing to a 5-7, 3-6, 7-6(4), 7-6(5), 6-3 defeat but the German said his issues began earlier.
"End of the second set I started to lose energy. I started to not feel so fresh anymore," Zverev told reporters. "I got a bit sick after the Alcaraz match with a bit of fever so that didn't help the recovery and I did play quite a lot.
"Against him (Medvedev), it's impossible to play when you're not 100% physically, because he's literally someone that really doesn't give you anything.
"He makes you work for every single point and once you can't really do that anymore, it becomes difficult. I was close in the third and fourth sets, but I wasn't the same player as I was the first two sets anymore. I was just hanging on."
There were many frustrating moments for Zverev during the match, including one where he smashed the net with his racket at 2-2 in the decider after missing a volley.
He was also asked about his defeat from two sets up in the 2020 US Open final by Dominic Thiem, but said Friday's loss was different.
"It's more frustrating that I didn't feel 100% physically. It took the chance away," Zverev said. "I lost it because of a physical state, not because of tennis."
He said an upcoming court case in Germany on physical abuse charges had not affected his concentration.
Zverev, who rejects the allegations, is due to appear before a Berlin court on May 31st on charges of abusing his former girlfriend.
"I have said it before: Anyone who has a semi-decent IQ level understands what's going on," Zverev said. "I hope that most of you guys do. I'm fine with it."
