Already a successful businessman, Cartwright was elected to the Parliament of the united province of Canada as an independent Conservative in 1863. After the Dominion of Canada was created in 1867, Cartwright disagreed with the financial policy of the Conservative Party leader, Sir John A. Macdonald, and became an independent.

From 1873, when he joined the Liberal Party, to 1878, he served as finance minister in Alexander Mackenzie's government. As chief financial spokesman during the Liberal opposition (1878–96), he advocated unrestricted reciprocity with the United States. He was knighted in 1879. From 1896 to 1911 he was minister of trade and commerce in Sir Wilfrid Laurier (Laurier, Sir Wilfrid)'s administration. He retired to the Senate in 1904, keeping a portfolio in the Cabinet and serving as premier during Laurier's absences. In 1909–11 he was government leader in the Senate.