The 42-year-old bowed out in the second round of the singles at Wimbledon last year and has only been involved in one other match since, which has sparked talk of retirement.
But a surprise wild card announcement earlier in the week saw the American back on the London lawn and teaming up with Murray, three years since their siblings Serena Williams and Andy Murray paired up in SW19.
And a 6-3 6-7 (3) 6-3 victory over Michael Venus and Alicja Rosolska ensured the pair continued to fly the family flag at Wimbledon after Andy and Serena made early exits from the singles.
The elder Williams sister partnered Nick Kyrgios at this tournament in 2021, but failed to play at all during the opening six months of this year and went on to miss the Australian Open and Roland Garros for the first time in a decade.
With the scheduled Court One action finished by 7pm, it allowed for one of the sport’s most decorated stars to return on one of the biggest stages.
Given Williams’ time away, it was understandable there would be rustiness but she appeared frustrated at her level during the opening exchanges.
A 116mph ace helped settle any nerves for the veteran, who battled for eight minutes before she held her first service game.
Regular chats took place with Murray, a hugely successful doubles player, and a first break was followed by two big Williams volleys to keep them on track for an opener that would be clinched in 39 minutes.
Another winner at the net by Williams earned an early break in the second but Rosolska and New Zealander Venus immediately hit back.
With Court One now filling up to see the comeback of the Florida right-hander, a winner of 23 grand slams in total but never the Wimbledon mixed doubles, a party atmosphere developed and a Mexican Wave delayed the beginning of the eighth service game in the second set.
It failed to distract Williams but she was sprawled on the floor minutes after a big hold following an attempted volley.
Rosolska’s impressive play at the net had sent her opponent to the ground and alongside doubles partner Venus they edged the tie-breaker to force a decider.
A delay occurred in order to close the Court One roof before Williams set about marking the 24th year she has played at Wimbledon with a victory.
It was quick hands by the American which saw her fire down a volleyed winner to break early in the third and a pep talk helped settle Murray following back-to-back double faults.
The Scot had no such issues next time and a 119mph ace helped him serve out for the match to send the new team into the last-16.
Williams embraced her partner at the net after two hours and 18 minutes of action on her comeback appearance having celebrated yet another successful result at Wimbledon.