The Serie A outfit started with Mertens on the bench, eventually introducing him when trailing 2-0, and the Belgium international won the penalty which Arkadiusz Milik converted.
But Napoli and Mertens could not force an equaliser and manager Sarri explained his decision, insisting it could have paid dividends had Facundo Ferreyra not nodded in a second for Shakhtar.
"[On Tuesday] I was accused of not making enough changes; now I am accused of too many," he said. "Dries is extraordinary and we don't leave him out lightly, but pace is his greatest strength and he can't have 50 to 55 games per year.
"He was coming off international duty, too, so we decided to rest him and let him come on later.
"If we had managed to keep it at 1-0, he could have got us the equaliser. He has certain characteristics and qualities so it's not easy to leave him out, but sometimes we have to."
Sarri believes the result can serve as a reminder that Napoli faces a tough ask in progressing from Group F, which also includes Manchester City and Feyenoord.
"We must not forget that we lost 2-1 at the home of the seeded team in this group," he said. "If anyone thought the Champions League would be a walk in the park for Napoli, they have their feet back on the ground now."
Despite a disappointing Napoli display, Shakhtar manager Paulo Fonseca felt his side deserved credit for its own performance.
"To Napoli, I say that it is not fair to say that they took the wrong approach to the game," he told a post-match news conference.
"From my point of view, we were good at cancelling out their strengths. We won against a very, very competitive opponent - and it was on merit."