Venus, seeded 16th, powered through the first set but appeared to lose energy toward the end of the second in broiling conditions inside the newly built Louis Armstrong Stadium.
The 38-year-old American said the crowd's encouragement had helped her.
"I felt the energy, definitely," Venus said. "That love-40 game at four all was not looking good and you guys really got me through that."
Asked about the possibility of a match-up against her sister, Venus said it was a tough draw.
"(Serena is) definitely fully capable of winning tonight's match," she said. "So hopefully I'll see her Friday.
"Obviously, it's early in the tournament, so both of us are going to be looking forward to continuing to play better."
Venus Williams won the U.S. Open in 2000 and 2001 while the 36-year-old Serena, seeded 17th, has lifted the trophy at Flushing Meadows six times.
(Reporting by Amy Tennery and Rory Carroll, editing by Ed Osmond)
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