Sabalenka’s pace and power was too much for world number 160 Iatcenko, who managed just three winners compared to the 24 put away by the top seed.
Iatcenko looked a bundle of nerves in the biggest match of her career, but composed herself to get on the scoreboard for 5-1 and immediately broke out into a relieved smile.
It was merely respite as Sabalenka held to love in less than 90 seconds to clinch the opening set.
Despite only being on court for 24 minutes, Iatchenko decided she wanted a bathroom break to change her kit – but more likely for a mental reset than anything else.
Sabalenka kept loose while she waited by practising her serves and maintained her rhythm as she surged a double break ahead for 3-0 in the second set.
It was not all plain-sailing for Sabalenka as she lost serve in a sloppy fourth game, but reasserted her authority with two more breaks as Iatchenko was taught a harsh lesson.
The Russian can console herself with the knowledge she has gained valuable experience against the world number one on the biggest court on the planet – and a bumper paycheck.
Coming into the US Open, she had earned $300,000 (£220,000) in her career but takes another $190,000 (£140,000) home from New York to reinvest into her future.
Earlier on Wednesday, third seed Pegula continued her quest for a maiden Grand Slam singles title with a comfortable victory over fellow American Sofia Kenin.
Pegula also has a shot of replacing Sabalenka as world number one if she wins the title, as does fourth seed Coco Gauff, and kept her dream alive with a 6-3 6-1 win.
There were also straight-set wins for Wimbledon runner-up Karolina Muchova, two-time major semi-finalist Marta Kostyuk and teenage American sensation Iva Jovic as the patten of few shocks in the women’s draw over the opening two rounds continued.