The 34-year-old beat Angelique Kerber in straight sets as pop superstar Beyonce and her husband Jay-Z watched on from her player's box.
Kerber was bidding to upset Williams for the second time in seven months, after stunning her prestigious opponent 161 days ago in the Australian Open final.
But there was no chance of a repeat this time round against the resilient Kerber.
Serena Williams insisted she was not focused on No. 22.
In fact, there was nothing most players could do - male or female.
To put that in context, Andy Murray averaged a speed of 118mph in his semi-final win over Tomas Berdych on Friday.
"Because so many things were underlined, the calendar slam, the 22nd, the fact that it was in NY, all those things together, this hurt her much too much and the other losses were a effect of this one", said Mouratoglou.
Kerber had stopped Williams in the Australian Open final in January to win her first grand slam title.
But she was not to be denied here.
The top seed had to recover from 15-30 down to hold for 6-5 with her eighth ace.
Speaking on court after the win, Serena said, "it's been incredibly hard not to think about it (the record)".
"It makes the victory even sweeter to know how hard I've worked for it". It's such a great feeling to be out here.
"I love playing out here on Centre Court, it just inspires me so much to be here".
"Margaret's got 24. So if she can keep her motivation and stay healthy maybe she'll be our greatest ever".
But that Roland Garros loss to Spain's Garbine Muguruza finally snapped her out of the brain fog that had plagued her since last September when her pursuit of the calendar Grand Slam ended with a shock Flushing Meadows defeat by Roberta Vinci.
For American tennis fans watching back home, Williams' win was a needed one. "Thank you for being out here to see number 22".
"It's awesome. I'm just so excited".
Her match complete, the crowd roaring its approval from the stands of Centre Court, Williams beamed and raised her arms.
Kerber simply had no answer to Serena's huge serve, despite a courageous effort from the German, with two breaks enough to secure Serena victory 7-5, 6-3.
"You can find a lot of terrific physical athletes, you really can".
Angelique Kerber of Germany returns to Serena Williams of the U.S during the women's singles final on day thirteen of the Wimbledon Tennis Championships in London, Saturday, July 9, 2016. Babos has never won a major doubles trophy; she was the runner-up with Kristina Mladenovic at Wimbledon in 2014. Congrats, you deserve it.
Kerber, 28, was the outsider but buoyed by her win over Williams in Melbourne, and the swirling wind added another element of uncertainty to the final.