Rain eventually arrived on the opening day of the tournament, suspending play on the outside courts, but not before Ukraine's Marta Kostyuk and Elina Svitolina also made strong starts to their US Open campaigns, with Kostyuk cruising past Australian qualifier Storm Hunter before ninth seed Svitolina took control against Argentina's Solana Sierra.
The world No.3 Pegula 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.
"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, in which 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, when 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.
Kostyuk launched her latest bid for a maiden Grand Slam title by breezing past Australian Hunter 6-4 6-1.
After stumbling at this year's Australian Open, Kostyuk has been in sublime form at the Grand Slams, making the semi-finals of the French Open and Wimbledon to arrive at Flushing Meadows as a genuine contender in the women's draw.
The 11th seed got down to business quickly once the match began and powered to a 4-1 lead before overcoming a wobble to close out the first set when Hunter produced a double fault on set point.
Kostyuk tightened her grip on the clash in the second set, breaking early and never allowing Hunter a route back into the match as she wrapped up victory in 67 minutes.
"I'm very happy to be back to this amazing place," Kostyuk said on court.
"It's not easy to play a qualifier, they've played a whole tournament (already). I'm very happy with my performance today. I try to keep myself grounded. There's still a long way to go, I'm enjoying my tennis."
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