Then, with Muguruza serving to stay in the first set at 5-4 down, came a 19-shot rally that changed everything.
Williams lost it as she dumped a forehand into the net, and was never the same player again.
It was all Muguruza after that, taking nine straight games to win her first Wimbledon crown, 7-5 6-0, and become the first player in history to defeat both Williams sisters in grand slam finals.
What looked like a classic Wimbledon final after the first set turned into an anti-climax when Muguruza won the second, and the championship, 6-0 in 26 minutes on a challenge in front of a stunned Centre Court crowd.
"It was my hardest match today," said Muguruza, as former Spanish king Juan Carlos watched from the royal box. "I grew up watching her play."
Williams' stunning collapse in the second set capped an emotional few weeks for the former top-ranked American, who had been involved in a car crash last month at home in Florida in which a man eventually died.
On July 8, Florida police said a newly surfaced video showed Williams "was acting lawfully" when she steered her car into a crossing before the fatal collision with another car on June 9, the Reuters news agency reported at the time.
"I try to do the same things you do, but I think there will be other opportunities" Venus said at the trophy ceremony, when asked if she missed her sister and last year's winner, Serena Williams, who is at home awaiting the birth of her first child.
Muguruza's triumph comes two years after she lost to Serena in her maiden grand slam finals at the All England Club.
Six weeks ago, Muguruza crashed out of the French Open in tears, losing her Roland Garros crown in front of a hostile crowd rooting for her opponent and not many people would have bet on her winning the title on the Wimbledon grass.
For her temporary coach, Conchita Martinez, it must have been a case of deja-vu. In 1994, Martinez spoiled the party for Martina Navratilova, who had been trying to win her tenth Wimbledon crown at the age of 37.
"She just told me to go out there and forget about all of this," Muguruza said in a news conference. "Try to think it's another match."
With Muguruza's traveling coach, Sam Sumyk, absent from Wimbledon, Spanish Fed Cup captain Martinez had guided her at the All England Club.
It appeared Martinez had a calming influence on the 14th-seeded Spaniard, one of the game's hardest hitters who is capable of beating anyone when she in full flow but had struggled with pressure since winning her first major at the French Open last year.
When Muguruza was dethroned in the fourth round of the French Open in a tempestuous match against by France's Kristina Mladenovic, not many experts would have expected her to recover this quickly.
But her confidence increased with each round won and, after beating women's top seed Angelique Kerber in the fourth round in a thrilling encounter, Muguruza started to believe.
Williams had started off the final with an ace and easily held with a blistering forehand down the line, as the sound of her shots reverberated under the roof of Centre Court on a rainy day in southwest London.
Playing in her first final since she won Roland Garros last year, Muguruza started nervously as she produced a double fault in her first service game.
With both women playing first-strike tennis, Williams stood slightly closer to the baseline, thumping winners as she held to love for a 3-2 lead and then set up her first break point with a forehand passing at full stretch in the next game.
But she was unable to convert it, dumping a forehand into the net, and Muguruza ended up holding.
In the next game, Williams held despite serving three double faults, saving a break point with a 106 miles-per-hour second serve.
Serving to stay in the set at 5-4 down, Muguruza gifted Williams two set points with a couple of forehand errors.
Targeting her opponent's forehand relentlessly, Williams failed to take the first set point as she put a forehand into the net after the longest rally of the match at 19 shots.
After Muguruza saved the second set point with a huge serve, she held with an error and all of a sudden, Williams started to look vulnerable.
"Definitely would have loved to have converted some of those points," Williams, who made 25 unforced errors, said in a news conference. "But she competed really well. So credit to her. She just dug in there and managed to play better."
Completely losing her way on the forehand, Williams, who had been diagnosed with the energy-sapping Sjogren's syndrome in 2011, got broken on the second break point with a wayward forehand that sailed over the baseline.
Serving for the set at 6-5, Muguruza set up two set points with a defensive backhand lob that seemed to go out. Williams chased it, but then let it go, and saw it land on the baseline.
"Vamos!" shooted Martinez from the players' box.
Muguruza missed the first set point as Williams drilled a forehand she failed to control, but took the first set when the American hit her 15th unforced error of the match.
"When I had those set points against me, I'm like, Hey, it's normal, I'm playing Venus here," Muguruza said. "So I just keep fighting. And I knew that if I was playing like I was playing during the two weeks, I was going to have eventually an opportunity. So I was calm. If I lose the first set, I still have two more. Let's not make a drama."
The momentum now completely with the Spaniard, she went up a double break in the second set as Williams struggled to find her range and sunk to the grass, holding her head in her hands after she crossed the finish line on a challenge.
"Not an ideal scoreline," said Williams about losing her first set to love at Wimbledon in 20 appearances.
"Very satisfied because I never knew how it was going to go because I was very nervous," Muguruza said. "I wanted it to go my way. I was doing everything I could to be prepared. Once you step on the court, you see the crowd, you see the final, you see I'm here playing another Wimbledon final. So very satisfied the way I handled it."
As for Williams, also a losing finalist to her sister in Australia in January, she will leave Wimbledon in the knowledge she is back in the mix when it comes to playing for the sport's biggest titles.
The US Open starts at the end of August, and there is no reason to think she won't be competing for the trophy once again.
"I'm in good form," she said. "I've been in a position a lot of times this year to contend for big titles. That's the kind of position I want to keep putting myself in. It's just about getting over the line. I believe I can do that."