The No. 1-ranked and No. 1-seeded Williams has faced American opponents in all three of her matches this week while extending her overall winning streak at Flushing Meadows to 17.
Williams had some trouble dealing with the whipping wind in Arthur Ashe Stadium but eventually took control against Lepchenko, a 2012 Olympic teammate and occasional practice partner.
Williams, a 17-time Grand Slam singles champion, is hoping to avoid her first season since 2006 without reaching at least one major final. She lost in the fourth round at the Australian Open, second round at the French Open, and third round at Wimbledon.