After graduation from the East India Company's college at Haileybury in 1834, Frere began his long career in the Indian Civil Service. He was chief commissioner of Sindh (Sind; now in Pakistan) from 1850 to 1859, where he did much to foster the economic development of the region. During the Indian Mutiny of 1857–58 the Sindh remained relatively quiet, enabling Frere to send troop reinforcements to the neighbouring Punjab. He was rewarded with a knighthood and a place on the viceroy's council at Calcutta (now Kolkata (Calcutta)), where he sat from 1859 to 1862.

After serving as governor of Bombay (now Mumbai) for five years, he returned to England as a member of the India Council (1867–77), in which posts he concerned himself with the development of Indian agriculture and communications and with educational improvements. He was created a baronet in 1876.

Lord Carnarvon, the British colonial secretary, sent Frere to the Cape Colony as governor and high commissioner in 1877 to carry out the planned confederation of British South Africa and the Boer republics. When he landed at Cape Town, Frere found the colony in turmoil. The colonists were unsympathetic to Carnarvon's plans, and the Transvaal Boers, whose lands had just been annexed by the British, were leaning toward independence rather than federation. Carnarvon's resignation in January 1878 further weakened Frere's position, and Frere did little to calm matters. After being convinced that the Zulu were an obstacle to federation, he provoked a war with them in December 1878. The Zulu War ended in a British victory, but the shocking defeat of British forces at Isandhlwana (Jan. 22–23, 1879) and the war's high cost led to Frere's official censure. He was recalled after federation talks collapsed in August 1880.