Birrell wore down Croatian Petra Marcinko 3-6 7-6 (7-4) 6-3 to finally reach the Open's second round after losing all three of her previous tournament openers at Flushing Meadows in 2023, 2024 and 2025.
Resurgent veteran James Duckworth also advanced with a mighty four-set upset win over 2026 French Open semi-finalist Matteo Arnaldi, the men's 30th seed.
After climbing to Australian No.2 this year behind only world No.7 Alex de Minaur, Duckworth continued his hot run with a 5-7 6-3 6-2 7-6 (10-8) comeback victory.
The 34-year-old has now finally reached round two at all four grand slams and next faces China's Yibing Wu for a place in the last 32.
Birrell and Duckworth follow WA rising star Taylah Preston in progressing, with three more Australians in action later on Monday (Tuesday AEST).
Birrell was forced to return to court 7 following a nervy 14-hour rain delay.
After surviving a match point in the 12th game of the second set on Sunday night, the 28-year-old was still trailing by a set and a mini break in the second-set tiebreaker before rallying to post one of the most satisfying wins of her career.
The Gold Coaster had lost in straight sets to Marcinko on grass at Eastbourne two months ago, having dropped the opening set 6-0 to the Croat in their first meeting which Birrell won in Texas in February.
The reward for Birrell's resistance is a showdown with Russian world No.19 Ekaterina Alexandrova and a guaranteed $US190,000 ($A265,000) pay day - or more if she wins again on Wednesday (Thursday AEST).
While Birrell and Duckworth marched on, Aleksandar Vukic was unable to win his own weather-delayed epic against Rei Sakamoto.
Sakamoto was up a break deep in the deciding set when their battle resumed, and the Japanese quickly won six more points on serve, without dropping any, to close out a 6-4 6-7 (5-7) 6-4 3-6 6-4 victory.
Alexei Popyrin, Rinky Hijikata and Maya Joint are also playing for second-round berths on day two at Flushing Meadow.
Popyrin takes on former semi-finalist Grigor Dimitrov, who had to qualify this year after being out injured. Rinky Hijikata also has a tough one against third seed Felix Auger-Aliassime and Joint is up against the much-fancied Liudmila Samsonova.
Sixth-seeded de Minaur opens his title quest on Tuesday (Wednesday AEST) against Italian qualifier Andrea Guerrieri.
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