Mbappe came off the bench in the 65th minute as defending champion PSG was downed 1-0 in Ligue 1 on Sunday (AEDT).
Making matters worse for PSG, Neymar was carried off on a stretcher in the closing stages after a tackle that saw Thiago Mendes sent off.
Asked about Mbappe starting on the bench, PSG head coach Tuchel said the star was at risk of injury.
"For Kylian, it was the medical recommendation," he said.
"He couldn't play for more than 25 minutes. He played 30 minutes, that was already too much. The medical staff said no for him to start the game, and no for more than 25 minutes.
"He was in a red zone and was at risk of injury."
Neymar was involved in only one shot against Lyon (one chance created), his lowest tally in a Ligue 1 game he started since November last year.
Tino Kadewere's first-half goal was enough for Rudi Garcia's men, who are second in the table – equal on points with Lille and one ahead of PSG.
Tuchel said he would have taken a different approach to the game if he had noticed his team's tiredness.
"It's my fault, I didn't feel the fatigue yesterday and that's why I'm surprised with our performance, our mistakes and our spirit today," he said.
"If I had this feeling yesterday, I would have made changes to start with a different mindset. For me, this is the key."
PSG's busy run of games continues at home to Lorient on Thursday (AEDT).