He was first elected to the Ontario legislature in 1919 as a member of the United Farmers of Ontario and served as a Cabinet minister in the government of Premier Ernest C. Drury as Provincial Secretary and Registar. Following the defeat of the UFO-Labour government in 1923, Nixon sat as a Progressive MPP becoming the leader of the small Progressive bloc (as most UFOers now called themselves) ater the 1929 election. Mitchell Hepburn, a farmer, became leader of the Ontario Liberal Party and Nixon led his Progressive remnant into an alliance with Hepburn's party. In 1934, Nixon and his followers ran as Liberal-Progressives helping bring the Hepburn to power in 1934. He ran again as a Liberal-Progressive in 1937.

Nixon resumed his old Cabinet position of Provincial Secretary and Registrar in the Cabinets of Hepburn and, his successor, Gordon D. Conant, who resigned as Premier after only six months due to serious divisions in the party. Nixon was chosen as Liberal leader and Premier in May 1943 but his government was unable to win the election held three months later.

Harry Nixon remained a Liberal MPP until his death in 1961. His son, Robert Nixon succeed him as MPP and later became leader of the Liberal Party but never Premier. He served as Treasurer in the Cabinet of David Peterson from 1985-1990. Harry Nixon's granddaughter (and Robert Nixon's daughter) Jane Stewart served as a Cabinet minister in the federal Liberal government of Jean Chretien.

Preceded by: Gordon Daniel Conant

List of Ontario premiers

Succeeded by: George Drew