The world number one saw off a fellow American for the third match running, with Lepchenko going down 6-3 6-3 at Flushing Meadows as Williams progressed to the fourth round.
Williams chalked up four breaks of serve and, despite losing the aces (3-6) and winners count (14-24), she wrapped up proceedings in 95 minutes at Arthur Ashe Stadium.
"My opponent today was spectacular. It was really a good match and it just shows how far Varvara has come, so I'm really proud of her," Williams said.
The win earned Williams a meeting with Estonian Kaia Kanepi, who accounted for 15th-seeded Spaniard Carla Suarez Navarro 7-5 6-0.
Williams made a swift start in New York, breaking Lepchenko to race out to a 3-1 lead in the opening set.
Lepchenko refused to surrender, however, as she fought back to level before a number of unforced errors handed Williams the advantage.
And the 17-time grand slam champion eventually served out the set after breaking for a 5-3 lead.
The second set was equally as entertaining, with Lepchenko fighting off six break points to stay in the match at 3-3.
Williams was not to be denied, though, with a break in the seventh game helping her to victory.