The 33-year-old American had some tough times towards the end from 20th seed Muguruza but ultimately won in one hour and 23 minutes.
She will head to the US Open next month aiming to complete the first calendar year Grand Slam of her career.
Muguruza was playing in her first Grand Slam final and took a 4-2 lead, before giving the top seed a immense panic by fighting back from a set and 5-1 down with two breaks of serve.
“There was definitely pressure towards the end,” said Williams, who also completed the ‘Serena Slam’ in 2003.
“Garbine started playing really well and I just had to think to stay out there and work really hard.
“I am having so much fun out on the court. Everyday is a pleasure to be playing and winning Wimbledon.”
A victory in New York would see the world number one match Steffi Graf’s calendar Slam of 1988, and tie the German’s open era record of 22 major wins.
Williams, who turns 34 next month, replaces Martina Navratilova as the oldest Wimbledon champion in the open era.
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