A career military officer, Amherst served in Europe during the Seven Years' War. He counted British prime minister Lord William Pitt among his friends. Pitt saw to it that Amherst was promoted to major general and put in command of an expedition against Louisbourg (in Nova Scotia, Canada). Amherst captured that French stronghold in 1758. He then assumed overall command in North America.

On Amherst's order, General James Wolfe captured Quebec in 1759. Amherst personally captured Montreal the following year, thus ending French control over what would become Canada. He became Governor General of British North America in 1761.

The new Governor General saw no reason to continue the French practice of allying with the native people. He dispensed of the practice of giving natives presents to ensure their loyalty. His "get tough with Indians" policy insulted and angered the native people. Many, in turn, united under Pontiac and captured several British forts in 1763. In letters to his subordinate officers, Amherst suggested they "inoculate the Indians by means of [smallpox infested] blankets." Several officers followed his suggestion, which resulted in smallpox epidemics among some native communities.

Amherst returned to England in 1763. He was appointed to the British Privy Council in 1772; four years later he was created Baron Amherst.