The No.6 seed won 6-2 7-6 (7-1) on Wednesday to advance to the last four at Melbourne Park for the first time, where she will meet 2022 Wimbledon champ Elena Rybakina.
The No.5 seed from Kazakhstan smashed down 11 aces in a comprehensive 7-5 6-1 victory over disappointing second seed Iga Swiatek from Poland.
Pegula has now won 14 of her past 15 matches against her compatriots, including straight-sets wins over McCartney Kessler, defending champ Madison Keys and now Anisimova at the 2026 AO.
The 24-year-old Anisimova did herself no favours with a string of untimely double faults late in the second set, before Pegula went up another gear in the tiebreaker.
"It's awesome," said Pegula.
"I've been able to go deeper at the US Open in the last couple of years, but here was the first slam that I really broke through at.
"And I was a three and then four-time quarter-finalist.
"It felt that it had to be coming to get into the semis because I feel like I play some really good tennis here and I like the conditions."
Anisimova got visibly frustrated as the unforced errors mounted up in the second set.
She reached her maiden grand slam finals in 2025 at Wimbledon and the US Open, while this year's run to the last eight was her best return in seven attempts at Melbourne Park.
In the earlier match, Rybakina again proved to be Swiatek's nemesis on the big stage, ending the world No.2's bid for a career grand slam with a straight-sets victory in the Australian Open quarter-finals.
Fifth-seeded Rybakina reprised her comprehensive win over the the Polish superstar at last year's WTA Finals.
It levelled their career head-to-head record at 6-all, with the Kazakh also coming out on top at their previous meeting at Melbourne Park back in 2023, when she went on to lose the final to Aryna Sabalenka.
"We know each other pretty well and I was just trying to stay aggressive," said the 26-year-old Rybakina.
"I feel like in the first set for both of us, the first serve was not really working.
"So we were trying to step in on the second serve, put pressure on each other, and I think in the second I just started to play more free, served better.
"I'm just really happy with the win."
Rybakina crunched down another 11 aces to take her tournament-leading tally to 35.
The Moscow-born talent dominated the winners' count 26-10 against the hugely disappointing Swiatek and also committed six less unforced errors.
Swiatek, 24, has six grand slam titles to her name - four of them coming at Roland Garros - but she will now be forced to wait at least one more year to complete the full set at the Australian Open.
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