The death leaves three northern white rhinos remaining on the planet.
The San Diego Zoo had lost its other northern white rhino, 44-year-old male Angalifu, to age-related causes in December last year.
The zoo had recently welcomed six southern white rhinos from South Africa as part of a novel conservation initiative to save the northern white rhino from extinction.
The six female southern white rhinos — all aged between 4 and 7 — will hopefully become surrogate mothers to northern white rhino embryos in the ambitious conservation effort.
Researchers at the San Diego Zoo Institute and collaborators "are developing reproductive techniques to develop northern white rhino embryos ... to be implanted in the southern white rhinos, which will serve as surrogate mothers."
"There are many challenges ahead, but researchers are optimistic a northern white rhino calf could be born from these processes within 10 to 15 years," the zoo said.
The zoo's genetics division has been preserving cell samples of wildlife in its so-called Frozen Zoo, including genetic material from 13 northern white rhinos.
If the reproductive technologies are effective, they could be applied to other rhino species, including the Sumatran and Javan rhinos — both also critically endangered.
Over the years, 94 southern white rhinos, 68 greater one-horned rhinos and 14 black rhinos have been born at the zoo.