The 45-year-old American recently returned from a 16-month layoff after a serious health scare and was among eight women’s wild card recipients named by tournament organisers.
Seven-time Grand Slam singles champion Williams will become the oldest singles entrant at the US Open since Renee Richards, who was 47 in 1981.
Williams underwent surgery last year to remove uterine fibroids and missed most of the season.
She made her comeback last month and became the oldest WTA match winner since Martina Navratilova at the age of 47 at Wimbledon in 2004, beating Peyton Stearns in the first round of the DC Open.
Williams, the 2000 Sydney Olympic singles champion, has also won five Wimbledon singles titles to go along with her 2000 and 2001 US Open triumphs.
She lost in the final in New York on her debut to Martina Hingis as a teenager in 1997. Venus also finished runner-up to younger sister Serena in 2002.
The most recent of her 49 WTA titles came in 2016 at the Taiwan Open.
Williams will also compete in the new-look US Open mixed doubles next week alongside Reilly Opelka.
France’s Caroline Garcia, 31, was given a wild card into what will be her final Grand Slam before retirement. Her best run at a major came when she reached the US Open semi-finals three years ago.
Americans Clervie Ngounoue, Julieta Pareja, Caty McNally, Valerie Glozman and Alyssa Ahn are other wild card recipients, as is Australian Talia Gibson.
On the men’s side, American players Brandon Holt, Nishesh Basavareddy, Tristan Boyer, Emilio Nava, Stefan Dostanic and Darwin Blanch all earned wild cards.
The final two went to France’s Valentin Royer and Australia’s Tristan Schoolkate.
The US Open singles main draw begins on August 24. (AFP)