The 33-year-old completed her second "Serena Slam" by swatting aside Muguruza 6-4 6-4, some 12 years on from the last time she hogged all of tennis' top prizes.
Now the oldest female major winner in the open era, Williams needs only retain her US Open title to claim the elusive calendar grand slam.
Record nine-time Wimbledon winner Martina Navratilova headed a cast list of former champions boasting a combined 17 All England Club triumphs watching on from the Royal Box as Williams faced Muguruza for the 2015 title.
Barcelona's Muguruza entered her maiden grand slam final and the biggest stage of her career, clinging to her 6-2 6-2 French Open demolition job on Williams in last year's French Open second round.
Russian teenager Maria Sharapova pulled off one of Centre Court's biggest women's final shocks by denying Williams a third consecutive Wimbledon crown in 2004.
Williams denied this year's showdown represented the potential for a similar upset in advance, claiming: "I think it's comparing apples to oranges, Garbine has been around for a while."
Incredibly, Williams fired three double faults in dropping serve in the opening game of the match.
The 21-year-old was just five when Williams claimed her first grand slam triumph, at the 1999 US Open, but maintained her unfazed opening by holding serve for a two-game lead.
Williams admonished herself, shouting: "What are you doing?" en route to holding serve and putting her stamp on the scoreboard.
Muguruza revved up her power game to fend off two break points in holding under pressure: but could not repeat that feat in her next service game.
Williams secured a foothold by breaking for four-all - then forced Muguruza to drop serve again to seal the first set 6-4.
Only Williams could win a set with relative ease despite a first serve success rate of just 49 per cent.
When the top seed and world number one resolved her service struggles after moving one set ahead, Muguruza was left with no outlet.
Williams broke twice in succession to lead five games to one in absolute dominance, to serve for the championship.
Those service wobbles came back as a double fault contributed to Williams facing three break points when she should have been serving out for the title.
A wild, wide forehand from Williams handed Muguruza a break back, allowing the Spaniard a reprieve.
Muguruza held to force Williams to serve for the match a second time.
Williams fended off three more break points, screaming "Where have you been?" when firing an ace to turn the tide.
Muguruza produced a fine forehand winner to deny Williams at Championship point - before blowing a fourth break point.
At the fifth time of asking Muguruza broke Williams once more however, to extend the contest still further.
The recovery was not to last: Muguruza's resolve then finally cracked, Williams breaking to love and converting her second Championship point.
After moving past sister Venus onto six Wimbledon titles, few will bet against her retaining the US Open title and completing that calendar slam.
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