Murray played his first competitive match since September on New Year's Day when he defeated James Duckworth in the first round in Brisbane, where he is unseeded having fallen to 240 in the world.
Medvedev was always likely to prove a stronger test of his credentials with the Australian Open just two weeks away, and so it proved as the young Russian overpowered the three-time Grand Slam winner.
ATP Cincinnati
Medvedev survives Fritz blitz to reach first Masters semi of the year
Medvedev fired 16 aces to set-up a quarter-final appointment with Canadian Milos Raonic on Friday.
“He served extremely well and I didn’t really get many chances on his service games,” Murray said. “And then on my own service games I made a few too many errors in the rallies, especially early on I was trying to play a little bit more offensive.
In the second set, I made a few too many mistakes, and obviously there was a period in the match from 5-5 where I lost six games in a row. When you play better players… they will expose any errors that you make in your game or any shots that you’re not hitting particularly well. And he did that.
Murray looked like he was struggling with his mobility during a difficult examination which saw him slump to 4-0 down in the second set before getting a game on the board.
After his win over Duckworth, an emotional Murray admitted that he could not be sure how much longer he has left in tennis due to his long struggles with his hip injury.

Emotional Murray: I don't know how much longer it's going to last

"It's my first match after a big break," he said on Tuesday. "It's not easy to sum up (but) it's been really hard the last 18 months, been a lot of ups and downs trying to get back on court.
"Being back now I am trying to enjoy it as much as I can, for as long as I can because I am not sure how much longer I have got."
US Open
US Open: Who's in? Who's out? Is Djokovic playing?
ATP Cincinnati
'I hate it' - Fritz, Medvedev give views on coaching rule ahead of clash