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.
The 28-year-old follows rising star Taylah Preston as the second Australian to progress after returning to court 7 on Monday (Tuesday AEST) following a nervy 14-hour rain delay.
After surviving a match point in the 12th game of the second set on Sunday night, Birrell 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 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.
Another four Australians are scheduled for day-two action, with Alexei Popyrin, Rinky Hijikata, James Duckworth and Maya Joint also playing for second-round berths.
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.
Duckworth faces Italian Matteo Arnaldi and Joint is up against the much-fancied Liudmila Samsonova.
World No.7 Alex de Minaur opens his title quest on Tuesday (Wednesday AEST) against Italian qualifier Andrea Guerrieri.
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