The world No.3 squandered eight break-point chances early in the first set as she opened the action on Arthur Ashe Stadium, before hitting her stride with 26 winners to just 14 from her opponent, closing it out with an unreturnable forehand.
She will have two days' rest under the 15-day schedule the tournament rolled out last year, and will next play the winner of a match later on Sunday on Ashe between American wildcards Venus Williams and Sofia Kenin.
"I was so nervous today," she said.
"(Now) I get to sit around the site and watch everyone else freak out."
Those nerves were apparent in a tricky opening set, where Ruse saved eight break points in a marathon third game but sent a shot wide to hand a break to Pegula in the fifth.
The Romanian held her arms aloft after surviving an entertaining cat-and-mouse exchange at the net to save break point in the seventh with a perfect backhand slice.
But Pegula took control of the match from there, cruising through her next service game before breaking Ruse with a forehand winner to close out the set.
Pegula sprinted through the next set, where she won all of her first-serve points and broke in the sixth and eighth games.
Meanwhile, twice grand slam winner Barbora Krejcikova became the first seeded player (27) to exit the tournament, saving six match points before succumbing to Uzbekistan's Kamilla Rakhimova 7-6 (7-4) 6-2 on the outer courts.
Rakhimova, who has never made it past the third round at the majors, will play the winner of Monday's match between Japan's Aoi Ito and Spain's Oksana Selekhmeteva.
Italian 19th seed Jasmine Paolini survived a scare to get past Slovenia's Veronika Erjavec 6-3 3-6 6-4 in the opening match at Louis Armstrong Stadium, firing off 36 winners to just 13 from her opponent.
The 2024 Wimbledon and French Open finalist will play the winner of a match later on Sunday between her compatriot Lucrezia Stefanini and Ukrainian Dayana Yastremska.
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