Pegula needed just 56 minutes to get past Kenin, the former Australian Open champion now ranked 110th, dropping just seven points on serve.
"I was just trying to stay focused on what I needed to do," said Pegula, who is among a trio of players who could supplant Aryna Sabalenka atop the world rankings in New York.
Pegula, who reached the US Open final in 2024, next meets another former finalist, Leylah Fernandez.
The Canadian breezed past Thailand's Mananchaya Sawangkaew 6-4, 6-1.
Defending champions Carlos Alcaraz and Aryna Sabalenka highlighted the day-four action.
World number one Sabalenka, gunning for a rare US Open three-peat, takes on 160th-ranked Russian qualifier Polina Iatcenko before second-ranked Alcaraz caps the night session against Portugal's Jaime Faria.
Alcaraz won his seventh major title at the Australian Open in January but arrived in New York an unknown quantity after a wrist injury forced a four-month layoff that saw him miss Roland Garros and Wimbledon.
US Open 2026
The US Open is the fourth and final Grand Slam of the tennis season, running from August 30th to September 13th. It is a hard-court tournament held at Flushing Meadows in New York City. Follow the links below for more information!
All you need to know | Men's singles draw | Women's singles draw | Latest US Open news
