On Tuesday, the No. 8-seeded Williams was forcefully dispatched by Johanna Konta of Great Britain 6-4, 6-2. It was the third major main-draw win of Konta's career, her first in Melbourne and without doubt the biggest of her life.
Was Venus' 16th Australian Open her final appearance?
Konta, who was born in Australia and moved to Great Britain at the age of 14, is, incredibly, now 4-2 against top-10 players. She said after the match that she was hoping to last more than an hour. As it turned out, she lasted 79 minutes.
"I have a very strong belief in the way I want to play, the way I want to think," Konta said in her on-court interview. "Sometimes you win, sometimes you lose, and today, I won."
Last year, Venus was the WTA's comeback player of the year, but Tuesday at Rod Laver Arena, she looked all of her 35 years as she labored around the court with a heavily taped left thigh and struggled with the serve (one ace) that was once her greatest weapon.
Venus, who turns 36 in June, was the oldest woman in the draw. She lost in the first round of a major for the eighth time in her career and for the third time Down Under, which makes that her worst effort at a Grand Slam.
She skipped her mandatory postmatch news conference, as she did at the 2015 French Open, and faces a fine of up to $20,000.
Meanwhile, second-seeded Simona Halep continued her early struggles at the Australian Open with a 6-4, 6-3 loss to Chinese qualifier Zhang Shuai. It was Halep's third loss in the opening round here in the past five years.
No. 15 Madison Keys, the 20-year-old Floridian, overcame some nerves in a first-set tiebreaker and defeated Zarina Diyas 7-6 (5), 6-1 in another bottom-half match. Keys was a semifinalist at last year's Australian Open. She lost to Serena Williams in the semis.
Venus is 0-2 this season but still seems capable of doing damage in the first week of Grand Slam events. Last year, she knocked off No. 6 seed Agnieszka Radwanska in the fourth round in Melbourne before losing to Keys in the quarters.
In theory, this was an upset. Konta is ranked No. 47 among WTA players. The tale of the tape going in was powerfully in favor of Venus Williams. She had won 47 WTA singles titles, compared to zero for Konta. Venus had brought home more than $32 million in official prize money -- more than $31 million more than her 24-year-old opponent. Not insignificantly, Venus has a 45-15 record at the Australian.
But Konta's victory wasn't exactly a surprise. Last year, she put together a sturdy run to the fourth round of the US Open and produced a lovely 16-match win streak.
The pair's only previous meeting last fall in Wuhan, China, saw Venus prevail 6-4, 3-6, 7-5 in a match that required a staggering 2 hours, 39 minutes.
As remarkable as Serena's 2015 season was (she turned 34 after the US Open), Venus, in her own more modest way, has been defying gravity too. By winning the year-end WTA Elite Trophy in Zhuhai, China, she collected her third title of the year and vaulted back into the year-end top 10 for the first time since 2010. She was the oldest woman to crack the top 10 since Martina Navratilova did so in 1994 at age 38.
Serena, of course, is the WTA's No. 1-ranked player, and every outing is a highly publicized adventure and media event for her. Venus' seven major singles titles are second to her sister's among active players, and she has grown accustomed to flying under the radar.
No one is expecting a major victory from Venus, who still suffers from the effects of Sjogren's syndrome, an autoimmune condition that leaves her prematurely tired. The last of her seven titles came at Wimbledon in 2008.
The third-seeded Muguruza, who has reached the fourth round on two of her three previous trips to Melbourne Park, broke Kontaveit three times in a 23-minute first set and got an early break in the second.
Also advancing on the women's side were No. 7 Angelique Kerber, No. 9 Karolina Pliskova, No. 11 Timea Bacsinszky, No. 18 Elina Svitolina, No. 19 Jelena Jankovic, No. 20 Ana Ivanovic and No. 21 Ekaterina Makarova, who beat Venus Williams in the first round here in 2014.
Information from The Associated Press was used in this report .