(CNN) -- Venus Williams' hopes of landing a fourth Miami Masters title were left in tatters after the U.S. star was forced to pull out with a back injury.
The seven-time grand slam champion withdrew ahead of her third round clash with fellow American Sloane Stephens Saturday.
Williams, ranked 18th in the world, had hoped to shake off the problem following her win over Japan's Kimiko Date-Krum.
It is the latest setback for the 32-year-old, who in 2011 fought back from Sjogren's syndrome, an auto-immune disease which causes fatigue.
"Yesterday I was having some pain, and then just wanted to see how I felt in the warmup -- just not able to play today," Williams told reporters.
"It's really disappointing. This is just the kind of tournament you want to play well at.
"But I have faced disappointments in my life and my career. It's not the first, probably not the last, just have to get through it and stay positive."
Williams now hopes to return to action in Charleston, South Carolina next month.
"I've dealt with injuries before in my whole career," she said. "I know how to hopefully recover quickly from them.
"I'm playing in Charleston, so that's really still my goal, to get ready to play there."
Her younger sister Serena went through to round four -- despite needing to resort to riding a bike to the event due to traffic problems.
The top seed and five-time Miami champion battled to a 6-3 6-3 win over Japan's Ayumi Morita to set up a meeting with Slovakian 13th seed Dominika Cibulkova.
Venus Williams wasn't the only big name to leave the tournament Saturday as Caroline Wozniacki crashed out after suffering a shock defeat by Spanish wild card Garbine Muguruza.
The World No. 9 was stunned 6-2 6-4 just a week after losing out in the final at Indian Wells to Maria Sharapova.
Muguruza, ranked 73rd in the world, will now take on Li Na in the fourth round.
Chinese star Li saw off American Varvara Lepchenko 6-2, 6-4 as she continued her comeback from injury.
The World No. 5 had been out of action for seven weeks after suffering an ankle injury during her Australian Open defeat by Victoria Azarenka.
But while Li is still in with a chance of glory, Azarenka's hopes are over after she was forced to withdraw with an ankle injury of her own.
"It was really obvious what the decision was couple days ago already," Azarenka told reporters. "I just wanted to give my 100 % possibility to play and today was my last test."
Maria Sharapova will be hoping to progress to the fourth round Sunday when she takes on fellow Russian Russian Elena Vesnina.
Sharapova, who won at Indian Wells last weekend, eased past Canada's Eugenie Bouchard 6-2 6-0 Friday following a power outage.
In the men's section, last year's runner-up Andy Murray eased into the third round with a comfortable 6-3 6-1 victory over Australia's Bernard Tomic.
Murray, who won the tournament back in 2009, will face Grigor Dimitrov next after the Bulgarian overcame Simone Bolelli.
"No matter how you start your match you need to make your opponent work hard," Murray told Sky Sports after seeing off a disappointing Tomic.
"I didn't hit it unbelievable today but I worked hard. Once I got the breakthrough he made mistakes. But it is unbelievably hot and windy.
"It's tough to feel comfortable, maybe more than my opponent because I am used to the court and the wind and the humidity."
Elsewhere, Sam Querrey survived an almighty scare to win his first match since becoming the U.S. No.1.
Querrey overcame Lukasz Kubot 4-6 6-3 6-3 to secure his place in the next round.
"I started out a little slow," he told the tournament's official website.
"He broke me the first game, but then he served really well rest of the first set.
"But after that, I felt pretty good second and third sets. I served big and hit my forehand well. I was pretty happy."
There were also wins for France's Jo-Wilfried Tsonga, Italy's Andreas Seppi, Belgium's David Goffin and eighth seed Richard Gasquet.
Sunday's action is set to include World No.1 Novak Djokovic, who is looking to win a fourth Miami Masters title
Djokovic, who destroyed Lukas Rosol 6-1 6-0 Friday, will take on India's Somdev Devvarman, currently ranked 254th in the world.
But one man who won't be on court is fifth seed Juan Martin del Potro after he was sent crashing out in the second round by Tobias Kamke.
Del Potro reached the final at Indian Wells last week, but was unable to see off 89th ranked Kamke.
"I was excited to play here, but [it was] just a bad day and he [played] really well," the Argentine told the tournament's official website.