India team manager Ranjib Biswal confirmed Tendulkar had returned home because of a right hamstring strain picked up in Saturday's dramatic victory over the Proteas in the second one-dayer.
India's cricket board says it will announce its 15-man World Cup squad on Monday. The World Cup, co-hosted by India, Sri Lanka and Bangladesh, begins on Feb. 19. The opening match is between India and Bangladesh.
Biswal said no replacement player for Tendulkar will be sent to South Africa, leaving India with just one recognized opening batsman — Murali Vijay — for the final three games of the series.
Openers Virender Sehwag and Gautam Gambhir and fast bowler Praveen Kumar were already ruled out with injury before the one-dayers began.
Tendulkar made a record-equaling 444th ODI appearance on Saturday as India clinched a one-run win at the Wanderers to level the five-match series 1-1. It was India's first ODI win in South Africa in 10 years.
The 37-year-old batsman made 24 but required treatment while batting and did not field. He will now miss the remainder of the series, which continues with a third match in Cape Town on Tuesday.
Tendulkar had been set to break the one-day international appearance record of Sri Lanka's Sanath Jayasuriya in that third ODI at Newlands.
