Born in Salisbury, Massachusetts in 1800, he was the son a wealthy ship builder and merchant. He entered Harvard University at the age of 13 and graduated in 1817. He was a teacher of mathematics there from 1820 to 1821, and was admitted to practice in the Massachusetts court of common pleas in December 1821. He began practicing law in Newburyport, Massachusetts in 1824.

After serving, as a Democratic-Republican, in the Massachusetts House of Representatives in 1825, in the Massachusetts Senate in 1826, and in the House again in 1828, he spent two years, from 1829 to 1831, in Europe, again served in the lower house of the state legislature in 1833 and 1834. In late 1834, he was elected by Whigs a representative to Congress.

Cushing served in Congress from 1835 until 1843 (the 24th, 25th, 26th and 27th Congresses). He was chairman of the U.S. House Committee on Foreign Affairs during the 27th Congress.

Here the marked inconsistency which characterized his public life became manifest; for when John Tyler had become president, had been read out of the Whig party, and had vetoed Whig measures (including a tariff bill), for which Cushing had voted, Cushing first defended the vetoes and then voted again for the bills. In 1843 President Tyler nominated Cushing for U.S. Secretary of the Treasury, but the U.S. Senate refused to confirm him for this office.

Cushing was, however, appointed by President Tyler, later in the same year. commissioner and Envoy Extraordinary and Minister Plenipotentiary of the United States to China, holding this position until March 4, 1845. In 1844 he negotitated the Treaty of Wang Hiya, the first treaty between China and the United States. While serving as commissioner to China he was also empowered to negotiate a treaty of navigation and commerce with Japan.

In 1847, while again a representative in the Massachusetts state legislature, he introduced a bill appropriating money for the equipment of a regiment to serve in the Mexican-American War; although the bill was defeated, he raised the necessary funds privately, and served in Mexico first as U.S. Army colonel and afterwards as brigadier-general of volunteers. He did not see combat during this conflict, and entered Mexico City with his reserve battalion several months after that city had been pacified.

In 1847 and again in 1848 the Democrats nominated him for Governor of Massachusetts, but on each occasion he was defeated at the polls. He was again a representative in the state legislature in 1851, was offered the position as Massachusetts Attorney General in 1851, but declined; and served as mayor of Newburyport, Massachusetts, in 1851 and 1852. (He had written a major history of the town when he was 26 years old.)

He became an associate justice of the Massachusetts Supreme Judicial Court in 1852, and during the administration of President Franklin Pierce, from March 7, 1853 until March 3, 1857, was 23rd Attorney General of the United States.

In 1858, 1859, 1862, and 1863 he again served in the Massachusetts House of Representatives. In 1860 he presided over the Democratic National Convention which met first at Charleston and later at Baltimore, until he joined those who seceded from the regular convention; he then presided also over the convention of the seceding delegates, who nominated John C. Breckinridge for the Presidency. Also in 1860 President James Buchanan sent him to Charleston as Confidential Commissioner to the Secessionists of South Carolina.

Despite having favored states' rights and opposed the abolition of slavery, during the American Civil War, he supported the Union. He was later appointed by President Andrew Johnson as one of three commissioners assigned to revise and codify the laws of the United States Congress. He served in that capacity from 1866 to 1870.

In 1868, in concert with the Minister Resident to Colombia, Cushing was sent to Bogotá, Colombia and worked to negotiate a right-of-way treaty for a ship canal across the Isthmus of Panama.

At the Geneva conference for the settlement of the Alabama claims in 1871-1872 he was one of the counsels appointed by President Ulysses S. Grant for the United States before the Geneva Tribunal of Arbitration on the Alabama claims.

On January 9, 1874 Grant nominated him for Chief Justice of the United States, but in spite of his great learning and eminence at the bar, his anti-war record and the feeling of distrust experienced by many members of the U.S. Senate on account of his inconsistency, aroused such vigorous opposition that his nomination was withdrawn on January 13, 1874.

From January 6, 1874 to April 9, 1877 Cushing was Envoy Extraordinary and Minister Plenipotentiary to Spain.

He died at Newburyport, Massachusetts, in 1879 and is buried in Highland Cemetery in Essex County, Massachusetts.

He published History and Present State of the Town of Newburyport, Mass. (1826); Review of the late Revolution in France (1833); Reminiscences of Spain (1833); Oration on the Growth and Territorial Progress of the United States (1839); Life and Public Services of William H. Harrison (1840); and The Treaty of Washington (1873).