The 23-time Grand Slam singles champion will be unseeded and starts against Zarina Diyas of Kazakhstan, currently ranked 53rd in the world.
Williams warmed up for her Californian outing with an appearance at the Tie Break Tens exhibition event at Madison Square Garden, reaching the semi-finals before losing to China’s Zhang Shuai.
After her coach Patrick Mouratoglou claimed the 36-year-old will be aiming to add more Grand Slam titles on her return, she appears confident ahead of her comeback.
Williams said: “I think everyone should have high expectations. That’s the message that I’m sending. You should always believe in yourself, even if no one else does.”
The American won her first match in New York 10-5 against Marion Bartoli, herself only recently back in tennis after four years out following an initial retirement after her 2013 Wimbledon victory.
Williams, who last appeared competitively as she won last year’s Australian Open, said she “can’t wait for the future” and added: “It was good. I wish I would have made a few more shots.”
Monday’s event featured eight players in the first all-female Tie Break Tens competition to take place in the United States.
Won by Ukrainian world No 4 Elina Svitolina – who claimed the $250,000 prize – she defeated Zhang 10-3 in the final.
Williams’ sister Venus also participated, losing her only tie against Svitolina, and is hopeful about her sibling’s impending Tour return.
As well as having her daughter in September, she developed several small blood clots in her lungs and her resumption of competitive action has been delayed longer than anticipated.
The sisters did play together in a Fed Cup doubles tie last month – losing in straight sets to Lesley Kerkhove and Demi Schuurs of the Netherlands – but there is more optimism now.
Venus said of Serena: “I mean, the matches are definitely a good way to know where you are, but obviously she knows how to play.
“She’s going to bring that instinct on the court with her, so I don’t think she’s too worried about that.”
Victoria Azarenka, who has not played since Wimbledon in 2017, will also be back on court at Indian Wells against Britain’s Heather Watson.