Mainoo was surprisingly withdrawn at the interval of the clash at the City Ground, with Scott McTominay introduced in place of the 18-year-old.
The two teams were level at 0-0 at the interval, but Forest scored twice in the second period, with Morgan Gibbs-White's effort proving to be the winner after Marcus Rashford had cancelled out an opener from Nicolas Dominguez.
Both of Forest's goals came from cutbacks, in areas where Mainoo was operating in the first half, and it had been thought that his substitution at the break was due to a fitness problem.
However, Ten Hag said during his post-match press conference that he decided to replace the teenage midfielder due to the amount of games he has played of late.
"He played the third game in a row, in this week, that's tough where he's coming from," Ten Hag told reporters. "I thought the energy was a little bit lower than in the other two games this week, therefore we brought some new energy in.
"I don't regret [the substitution]. I thought Scott, he brought energy, I think second half was much better [from] our side.
"I think the first goal, when you analyse it good, it went down the sides. Nothing to do with the central midfielder there. The second goal was a counter-attack, where I think it was a miscommunication, we had enough players.
"The second part of it [Gibbs-White's finish], in the first half, there were already some moments where Gibbs-White ran away, it was good play, but we should have tracked that."
Ten Hag also opened up on the "very disappointing" result, with Man United suffering their 14th defeat of the campaign, nine of which have come in the Premier League.
"It's clear the result is very disappointing, I'm also disappointed by the performance before half-time. We should have invested more in such moments," he said.
"We created less before half-time and we should invest more there, by quicker play and by movements. In the final third, it was not good enough, and we did not invest enough to create chances.
"So the first-half performance was not okay but the second half was better. In bad moments, we conceded the goals. In that moment, the game was ours and we went for 2-1, only to concede on the counter. Then we tried and had chances, as well at the end of the game, at the last whistle, with Christian Eriksen."
Man United will be bidding to bounce back from their latest disappointing result when they travel to Wigan Athletic in the third round of the FA Cup on January 8.