Serena's comeback to the game came to an end after she was beaten in straight sets by elder sister Venus Williams.
Veteran 8th seed Venus sealed their 29th meeting in singles competition after a comfortable 6-3, 6-4 win in the third round.
Serena, who returned to competitive tennis after a 15-month child birth lay-off, had won her first two games.
2018 Indian Wells round-up
Venus-Serena battle and the hype
A lot of hype and excitement was built up around the match between the two stalwarts of the game. The last time the duo met was in the 2017 Australian Open final. The sisters had boycotted the Indian Wells tournament for 14 years.
Federer safely through to Round of 16
Men's world No. 1 Roger Federer progressed to the Round of 16 after overcoming Serbia's Filip Krajinovic.
The Swiss maestro won his duel 6-2, 6-1 in a comfortable 58-minute long match.
Federer will next face France's Jeremy Chardy.
The 20-time Grand Slam champion has been in red-hot form this year.
He won the Australian Open and the Rotterdam Open.
Love Sports news?
Stay updated with the latest happenings.
Women's biggies Wozniacki, Halep progress
Women's world number 1 Simona Halep survived a scare to the reach the Round of 16 at the Indian Wells.
The Romanian came back from one set down to beat Caroline Dolehide 1-6, 7-6, 6-2.
She was joined by 2018 Australian Open winner and second seed Caroline Wozniacki.
The Dane came through in three sets 6-4, 2-6, 6-3 to overcome Aliaksandra Sasnovich.
Delhi Daredevils announce Gambhir as captain for IPL 2018
Squad analysis IPL 2018: Kolkata Knight Riders