After running a medical practice for several years, MacMillan entered politics in 1923 winning a seat in the provincial legislative assembly as a Conservative. In 1932 he became the province's first minister of health and education. As minister he rebuilt Prince of Wales College and the Provincial Mental Hospital which had both been destroyed by fire. He also secured a Carnegie Foundation endowment that enabled the government to establish a provincial library system.
When James D. Stewart became ill, MacMillan served as acting premier and then became Premier when Stewart died in 1933. MacMillan's government implemented relief programs and increasing government spending to help dampen the impact of the Great Depression. Nevertheless, his government was swept from power in the 1935 election which saw the Liberals capture every seat in the legislature. He returned to the legislature in 1939 and remained leader of the Conservative Party until the late 1940s and a member of the legislature until he lost his seat in the 1955 election.