The 23-year-old rhino was named Nikki and died Thursday at her indoor space at the Cincinnati Zoo & Botanical Garden.
Nikki was born at the Toronto Zoo in 1991 and later was moved to the Cincinnati zoo.
The zoo says it was a breakthrough when she was impregnated through artificial insemination. The first time ended with a stillbirth in 2008. The second time the calf died after birth in 2010.
Nikki's cause of death is unclear, but she showed signs of illness last month.
The zoo says there are 60 captive Indian rhinos in the U.S. and about 3,300 in the wild.