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The 23-time Grand Slam champion joins Roger Federer, Rafael Nadal and Novak Djokovic among the stars to have pulled out of the tournament, which gets under way on Monday with qualifying rounds.
"I am disappointed to withdraw from the Miami Open because of recent oral surgery," Williams said in a statement quoted by US media.
"Miami is a special tournament for me because it's my home and I am sad I won't be able to see the incredible fans this year, but I look forward to coming back soon," the former world number one said.
Williams' withdrawal is another blow to the tournament which was cancelled last year because of the Covid-19 pandemic.
The 39-year-old star is an eight-time winner in Miami and lives in Florida.
"We will certainly miss having Serena at this year's tournament and I know it was a very difficult decision for her," tournament director James Blake told the Miami Herald.
"She has won the Miami Open more than any player in history, has a home here in South Florida, and is always a fan favorite. We hope she is back on the court soon and look forward to welcoming her back here next year."
Former men's world number one Federer withdrew from Miami on March 2, and he was followed by Nadal and world number one Djokovic, who pulled out on Friday citing a desire to spend more time with his family.
"I decided to use this precious time at home to stay with my family," Djokovic said.
"With all restrictions, I need to find balance in my time on tour and at home. I look forward to coming back next year!"
With Williams absent, the women's tournament will be headlined by world number one Ashleigh Barty and Japan's world number two Naomi Osaka, the four-time Grand Slam champion.
The highest ranked player in the men's draw is Russia's world number two Daniil Medvedev while Alexander Zverev, winner of the ATP tournament in Acapulco, Mexico on Saturday also features.
This year's Miami Open meanwhile is taking place against a backdrop of declining Covid-19 numbers in the United States as the vaccine rollouts gather pace.
However authorities in Miami Beach imposed a state of emergency and a curfew in the tourist hotspot on Saturday to deal with rowdy throngs of people partying during spring break, amid fears of a possible Covid-19 resurgence.
Crowd capacity at the Miami Open is being strictly limited with most courts having no fans at all, and main courts only hosting a maximum of around 1,000 spectators per session.