After losing a close first set and battling bravely to come back from 5-1 down in the second, the 21-year-old Spaniard was eventually downed after one hour and 23 minutes of combat, to leave Williams to receive the acclaim of the Centre Crowd.
At 33 years and 289 days, Serena surpasses Martina Navratilova as the oldest player to win Wimbledon, and any of the other three Grand Slams, in the Open era.
Muguruza, born in Venezuela and raised in Barcelona, had insisted facing Serena was a task to be relished rather than feared.
She was proving true to her bold claim and, by the time Muguruza moved into a 4-2 lead, it seemed an epic shock was on the cards.
However, Serena had recovered from worse predicaments earlier in the tournament.
And with the pressure ratcheted up, the inevitable Serena break back arrived in the eighth game when Muguruza missed with a wild forehand.
Williams scented blood and Muguruza crumbled, a double-fault on set point gift-wrapping the lead to Serena in a set that had been the underdog’s for the taking.
Williams had won 28 of her last 30 tour-level finals, including her last nine at the majors, and, in her eighth Wimbledon final, she was finally back in that muscular groove.
Serena’s fierce grimace and clenched fist after breaking in the fourth game of the second set suggested the finish line was in sight
But, serving for the match with 5-1 and then 5-3 leads, Williams was gripped by a bad case of nerves and Muguruza broke twice to prolong the contest.
Finally able to compose herself, Serena broke in the next game to seal yet another legacy-defining success.
Serena’s sixth Wimbledon crown brought with it a slew of other remarkable landmarks that underline her credentials as one of the greatest female athletes of all time.
The American’s 21st Grand Slam crown and 68th tour-level title earned her a cheque for £1.8 million.
But it is her legacy rather than her bank balance that concerns Williams these days and she now holds all four Grand Slam titles at the same time – the rare ‘Serena Slam’ she last achieved in 2002-03.
Serena is the first woman to land the French Open and Wimbledon back-to-back since she last won that difficult double in 2002.
Lifting the Venus Rosewater Dish for the first time since 2012 also leaves Serena needing only to defend the US Open to become the first woman since Steffi Graf in 1988 to claim a calendar Grand Slam.
She is just one major title behind Graf on the Open era leaderboard and within three of all-time record holder Margaret Court’s tally of 24.
She is the first player since Graf in 1988 to win Wimbledon and the Australian and French Opens in the same year.
Given Serena’s 39-1 record in 2015 and her astonishing streak of 28 consecutive Grand Slam match victories, few would bet against the American making more history in New York in August.