With the loss, Halep once again fell one win short of rising to the top of the world rankings.
The Romanian, looking to supplant Karolina Pliskova from the top spot, entered the final without dropping a set all week but on Sunday her game fell apart.
Simona Halep, Garbine Muguruza
Image credit: Getty Images
Halep's second serve proved to be a liability, winning only 11 percent.
Spaniard Muguruza, who had failed to capture a title for more than a year following her triumph at last year's French Open, was now celebrating winning two trophies in as many months as she backed up her Wimbledon victory with her glorious run in Cincinnati.
She credited Sunday's win on saving three match points in her third-round encounter against American Madison Keys.
"The match with Keys gave me a lot of confidence," Muguruza told ESPN.
"I like the big matches. I believe I play well there. I’m happy to be there, happy to be in that situation.
"When I was a little girl I was dreaming to be there. That’s where I want to play."
But Muguruza declined to build up her chances for the US Open.
"The US Open is a very long tournament," said the tall 23-year-old. "It’s completely different. I’m just trying to play well."
Halep, who also squandered a chance to climb to the top of the world rankings when she was beaten in the French Open final in June, acknowledged she had performed poorly.
"I played so bad today and Garbine played so well," Halep, told the crowd. "I will come back next year and try to do better."