Russian 15th seed Svetlana Kuznetsova stunned 21-time Grand Slam champion Williams 6-7 (3/7), 6-1, 6-2 while British world number two Murray dropped a third-round match to Bulgarian 26th seed Grigor Dimitrov 6-7 (1/7), 6-4, 6-3.
Williams and Murray each made 55 unforced errors, fading in the third set when it mattered most.
“A lot of unforced errors crept in and he was a lot more solid than me,” said Murray, who had 22 unforced errors in the last set alone. “I made many more mistakes than usual, especially in the third set.”
Williams’ struggles prompted questions about her fitness and movement, irking the 21-time Grand Slam champion.
“I don’t think it’s appropriate to criticize my movement right now,” Williams said. “I did the best I could. I can’t win every match. These players come out and give their best. I have to give 300 percent every match.”
The 34-year-old American was seeking her ninth Miami crown but instead matched her earliest-ever exit from 2000 with a fourth-round departure.
“It’s obviously disappointing, but I have won here a lot, so it’s OK,” Williams said.
Also ousted were world number two Agnieszka Radwanska of Poland, eliminated by 20th-ranked Swiss Timea Bacsinszky 2-6, 6-4, 6-2, and Spanish fourth seed Garbine Muguruza, who fell 7-6 (8/6), 7-6 (7/4) to 13th seed Victoria Azarenka of Belarus.
Only two of the top 12 seeds — number two Angelique Kerber and number five Simona Halep — remain on the women’s side. Top-ranked Novak Djokovic is the last top-five man remaining and only three of the men’s top eight made the last 16.
Two-time Grand Slam champion Murray failed in his bid for a third Miami trophy and fourth final in five seasons.
The 28-year-old Scotsman dominated the tie-breaker but fell behind 4-0 in the second set and stumbled after leading 3-1 in the third, swatting a forehand long on match point to fall after two hours and 24 minutes.
“It’s the best result of the year for me,” Dimitrov said. “I just played better in the good moments. That was it.”
Williams, who said she was physically fine and not affected by the heat and humidity, arrived having lost back-to-back finals for the first time since 2004, falling to Germany’s Angelique Kerber at the Australian Open and Azarenka at Indian Wells.
“She struggled a little bit losing the final of the Australian Open, but she is still number one in the world,” Kuznetsova said. “I don’t see much to be depressed about.”
But intensity only increases as Williams prepares to defend French Open and Wimbledon crowns in the next few months.
“There are expectations,” she said. “There are also the expectations I put on myself. That’s pretty hard to live up to, the expectations I put on myself.”
Kuznetsova feels like champ
Kuznetsova, a two-time Grand Slam champion who lost eight of 10 prior matches to Williams, is starting to feel like she did when she won the 2006 Miami title.
“I have so many people saying, ‘Congratulations,’ I feel like I’ve won the title already,” Kuznetsova said.
Kuznetsova, seeded 15th, next faces 30th-seeded compatriot Ekaterina Makarova, who ousted Ukraine’s 12th-seeded Elina Svitolina 6-1, 6-4
Radwanska, the 2012 Miami champion, faded in the second set as well to Bacsinszky, a 2015 French Open semi-finalist.
Bacsinszky’s quarter-final foe will be Romania’s Halep, who eliminated 69th-ranked British wildcard Heather Watson 6-3, 6-4.
Next up for Azarenka is British 24th seed Johanna Konta.
And Australian Open champion Kerber of Germany will face US 22nd seed Madison Keys after dispatching Hungary’s Timea Babos 6-2, 3-6, 6-4.
Japanese sixth seed Kei Nishikori cruised into the fourth round by routing Ukraine’s 27th-seeded Alexandr Dolgopolov 6-2, 6-2.
“I played a very solid match,” Nishikori said. “It’s not easy when you’re in the top 10 and everybody is playing their best against you.”
Nishikori, the top-ranked player remaining in his half of the draw, plays Tuesday for a quarter-final berth against Spanish 17th seed Roberto Bautista Agut.