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’s 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.
“I can’t believe I’m standing here with another Serena Slam,” said Williams.
“I just never dreamed I would be out here still, let alone winning and having so much fun.
“It’s been such a pleasure to have played in front of this crowd for so long.”
Williams’s first Wimbledon title in three years moves her past sister Venus’ haul of five victories in SW19.
As if to illustrate her ever more obvious status as the greatest women’s player of all time, Williams departed Centre Court balancing the historic Venus Rosewater Dish trophy on her head.
Victory at Flushing Meadows at the end of the summer would bring Williams level with Steffi Graf’s 22 major titles, leaving only Margaret Court’s 24 for her to equal.
Only Williams could serve so poorly, produce so many unforced errors - and still win in straight sets.
Williams fired three double faults in dropping serve in the opening game of the match.
Muguruza was just five years old when Williams claimed her first grand slam triumph, at the 1999 US Open: that intimidating chasm of both experience and success eventually took its toll.
Williams admonished herself, shouting out “What are you doing?” en route to holding serve and finally 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.
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 - only in truth managing to prolong her agony.
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 to reach six Wimbledon titles, few will bet against her retaining the US Open title and completing that calendar slam.