It was a tough day for seeded players at the BNP Paribas Open, with Novak Djokovic and Naomi Osaka, the world's top-ranked players, ushered out in the desert.
After winning the Australian Open, Osaka shocked the tennis world by parting ways with her coach Sascha Bajin.
Osaka, meanwhile, was trying to find the positives after falling in the fourth round 6-3, 6-1 in just 66 minutes to a red-hot Belinda Bencic of Switzerland.
Bencic, 21, stunned two-time Wimbledon champion Petra Kvitova in the final of the Dubai Duty Free Tennis Championships last month to capture her first WTA title in four years. "But I feel pretty good right now, because I think, given the circumstances, I tried my best and I don't really have any regrets. Yeah, I think I did well for my first time".
She will have another shot at a top-10 player when she takes on hard-hitting world number five Karolina Pliskova, who smashed 13 aces to dispatch Anett Kontaveit 7-6 (0) 4-6 6-2 to reach the quarter-finals.
"He was aggressive in key situations and I couldn't execute", said Nishikori, who had his left calf taped.
But there were no tears on Tuesday as Osaka said she was adjusting to being the world number one and always having a target on her back.
The women's field lost its top two seeds as Romania's Halep, the 2015 Indian Wells victor, fell to Czech teenager Marketa Vondrousova 6-2, 3-6, 6-2.
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"I had never played (McHale) before, so you feel like you don't really know what's going to happen".
The seven-time major victor was broken early in both sets but she still managed to see off McHale in the pair's first meeting.
The win was 19-year-old Vondrousova's first over a top-10 player in six attempts. "So just things worked out for me".
Canada's Bianca Andreescu, 18, continued her remarkable season with a 7-5 6-2 win over China's Wang Qiang.
Vondrousova will go for another big win when she faces sixth-seeded Elina Svitolina, who battled to a 7-6 (10/8), 5-7, 6-4 victory over Australian Ashleigh Barty.
In other third-round action, three-time grand slam champion Angelique Kerber came from a set down to beat Russian qualifier Natalia Vikhlyantseva 3-6, 6-1, 6-3.
Seven-time grand slam victor Venus Williams also found it tricky facing fellow American Christina McHale for the first time, but she pulled back early breaks in each set to win 6-2, 7-5.