Serena, who turns 41 later this month, had earlier revealed she plans to "evolve" away from tennis after the US Open campaign. However, her dream run ended in the third round with a 7-5, 6-7 (4/7), 6-1 loss to Australia's Ajla Tomljanovic.
Serena had raised hopes of a stellar campaign after her second-round win over world number two Anett Kontaveit. But after her defeat in the third round, Serena said she was ready for life beyond the court.
"It takes a lot of work to get here. Clearly I'm still capable," she said. "It takes a lot more than that.
"I'm ready to, like, be a mom, explore a different version of Serena. Technically in the world I'm still super young, so I want to have a little bit of a life while I'm still walking."
Serena said she wanted to be remembered as a fighter and was proud of the impact she had on tennis.
"The fight, I'm such a fighter," she said when asked how she wanted to be remembered.
"I feel like I really brought something to tennis, a different look, the fist pumps, the just crazy intensity. Passion is a really good word."
Tiger Woods and former US First Lady Michelle Obama hailed Serena as "the greatest" as the tennis superstar headed into retirement.
"@serenawilliams you're literally the greatest on and off the court," tweeted Woods. "Thank you for inspiring all of us to pursue our dreams. I love you little sis!"
Michelle hailed Serena for her rise to stardom from the tough Californian neighbourhood of Compton.
"Congrats on an amazing career, @SerenaWilliams! How lucky were we to be able to watch a young girl from Compton grow up to become one of the greatest athletes of all time," tweeted Obama.
"I'm proud of you, my friend and I can't wait to see the lives you continue to transform with your talents."
NBA superstar LeBron James called Serena the GOAT (greatest of all time).
"Congratulations to you, you had an unbelievable career," James said in a video message.
"What you have done for sport, for women is unprecedented, it's been an honour to watch your journey and conquer all the goals you set out to do. Win, lose or draw, we knew you were the greatest."
A number of celebrities watched Serena's valiant fight on Friday. They included boxing great Mike Tyson, director Spike Lee, model Bella Hadid, singer Ciara, American sports stars Russel Wilson, Saquon Barkley and others.