In 1802 Clinton became a member of the United States Senate, but resigned in the following year to become mayor of New York city, an office he held from 1803 to 1807, from 1808 to 1810, and from 1811 to 1815. During his mayoralty he also held other offices, being a member of the state senate from 1806 to 1811 and lieutenant-governor from 1811 to 1813. In 1812, after a congressional caucus at Washington had nominated Madison for a second term, the Republicans of New York, desiring to break up the so-called Virginia dynasty as well as the system of congressional nominations, nominated Clinton for the presidency by a legislative caucus. Opponents of a second war with Great Britain had revived the Federalist organization, and Federalists from eleven states met in New York and agreed to support Clinton, not on account of his war views, which were not in accord with their own, but as a protest against the policy of Madison. In the election Clinton received 89 electoral votes and Madison 128.
As a member of the legislature Clinton was active in securing the abolition of slavery and of imprisonment for debt, and in perfecting a system of free public schools. In 1810 he was a member of a commission to explore a route for a canal between Lake Erie and the Hudson river, and in 1811 he and Gouverneur Morris were sent to Washington to secure Federal aid for the undertaking, but were unsuccessful. The second war with Great Britain prevented any immediate action by the state, but in 1816 Clinton was active in reviving the project, and a new commission was appointed, of which he became president. His connexion with this work so enhanced his popularity that he was chosen governor by an overwhelming majority and served for two triennial terms (1817-1823). As governor he devoted his energies to the construction of the canal, but the opposition to his administration, led by Martin Van Buren and Tammany Hall, became so formidable by 1822 that he declined to seek a third term. His successful opponents, however, overreached themselves when in 1824 they removed him from the office of canal commissioner. This partisan action aroused such indignation that at the next election he was again chosen governor, by a large majority, and served from 1825 until his death. As governor he took part in the formal ceremony of admitting the waters of Lake Erie into the canal in October 1825, and thus witnessed the completion of a work which owed more to him than to any other man. Clinton died at Albany, N.Y., on the 11th of February 1828. In addition to his interest in politics and public improvements, he devoted much study to the natural sciences; among his published works are a _Memoir on the Antiquities of Western New York_ (1818), and _Letters on the Natural History and Internal Resources of New York_ (1822).