Three-time defending champion Serena reached a Thursday semi-final against Italy's 43rd-ranked Roberta Vinci, who eliminated France's 40th-ranked Kristina Mladenovic 6-3, 5-7, 6-4.
Serena, who holds all four major trophies, moved two wins from completing the first calendar Grand Slam since Steffi Graf 27 years ago and matching Graf's career Open Era record of 22 singles titles, two shy of Australian Margaret Court's all-time mark.
Playing at a high level throughout, the sisters staged a classic at Arthur Ashe Stadium, which was jam-packed with fans and celebrities, including US Presidential hopeful Donald Trump and TV mogul Oprah Winfrey.
Serena fired 35 winners with 22 unforced errors with 12 aces, the last coming on match point. Venus had 24 winners, 15 unforced errors and eight aces.
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Three-time defending champion Serena, the younger sister by two years at 33, improved to 53-2 on the season and took a 16-11 edge in the sibling rivalry, including an 9-5 advantage in Grand Slam meetings and a 3-2 lead in US Open results.
Serena, seeking an Open Era record seventh US Open crown overall, is on a 33-match Grand Slam win streak and a 26-match US Open win streak, her last loss on the Flushing Meadows hardcourts coming to Samantha Stosur in the 2011 final.
Venus, seeded 23rd, sought her third US Open crown after 2000 and 2001 to add to a Slam trophy haul that also includes five Wimbledon titles, the most recent in 2008.
"She's the toughest player I've ever played in my life and the best person I know," Serena said of Venus.
"It's going against your best friend and the best competitor in women's tennis.
"When I'm playing her I don't think of her as my sister. When you're in the moment you dont really think about it. For us it's a really great honor.