Williams has been stuck on 21 since winning Wimbledon last summer and fell just short again at the French Open with a 7-5 6-4 final defeat by Garbine Muguruza.
In the last three slams, Williams has lost once in the semi-finals and twice in the final, and Mouratoglou feels history is weighing heavily on her.
The Frenchman, Williams' coach since 2012, said: "There is a very high level of expectation and tension on this 22nd grand slam. It doesn't make her play bad but maybe not aggressive enough to win it."
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Speaking of her attempts to equal the number of grand slam victories of Chris Evert and Martina Navratilova, he said: "This 22nd is difficult, but the 17th and 18th were difficult, too. It's normal. You cannot play a grand slam final for history the same way as any other."
"It's going to take the time that it's going to take but we're going to do it, we're going to make it. The good thing is we have many occasions because she's in finals almost all the time. I don't doubt she will achieve it."
Mouratoglou had said before the match that it was on Williams' racket, a comment that may well have provided the powerful Muguruza with a little extra motivation.
He stuck to his guns but admitted the Spaniard surprised him with the confident way in which she finished the match, serving out to love after Williams had saved four match points.
He said: "She deserves 100 per cent to be a grand slam champion because, when you're able to be hitting every shot to win, it's something that a lot of players even who've been number one were not able to do in grand slams.
"When you're able to finish the way she finished in the last game, it's a second reason to say that she deserves it.
"I was a little bit surprised. Not because I didn't think she was able to do it but more because what I saw during the match was a lot of tension on her side.
"After having match points and Serena coming back to 4-5, I expected more tension but she didn't do it. Well done."
Muguruza's coach Sam Sumyk was also concerned it could have been a turning point, saying with a smile: "How can you ask for a better ending? She did a similar thing in her semi-final against Sam Stosur, she had an incredible last game. I thought about it at that moment, 'Oh it would be nice to see it again.' It was just silly thoughts but she did it."
Sumyk, another Frenchman, began coaching Muguruza last September.
Her form in 2016 until these two weeks had been shaky to say the least but Sumyk had faith she could produce at Roland Garros.
He said: "I always believed it would be possible to have a great two weeks here. To lift the trophy at the end? Maybe not.
"I'm proud of her and I'm very happy for her because it's not easy. You media, you call it, you say this one should be the next one, but until it's done, it's complicated.
"You have all these expectations and it can mess up a little bit your brain. Now it's done, finished, her name's not going to be on a list of potential grand slam winners. We can move on."
Muguruza reached her first grand slam final at Wimbledon last year and Sumyk, who coached Victoria Azarenka to two slam titles, is confident his new charge can also be a multiple champion.
"I think she has the desire," he said. "Hopefully she will be again in a position to be in finals and win another big title, because honestly this is awesome."
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