Born in West Liberty, Ohio County, Virginia (now West Virginia). After studying at Ohio University and reading law under Philemon Beecher, Ewing commenced the practice of law in Lancaster, Ohio in 1816. As a colorful country lawyer, he was elected to the U.S. Senate in 1830 as a Whig and served a single term. He was unsuccessful in seeking a second term in 1836. Ewing served as Secretary of the Treasury from March 4, 1841-September 11, 1841, serving under Presidents William Henry Harrison and John Tyler.

Ewing was later appointed to serve as the first Secretary of the Interior by President Zachary Taylor. Ewing served in the position from March 8, 1849-July 22, 1850 under Taylor and Millard Fillmore. As first secretary, he consolidated bureaus from various Departments, such as the Land Office from the Treasury Department and the Indian Bureau from the War Department. The bureaus were being kicked out of their offices as unwanted tenants in their former departments. However, the Interior Department had no office space, so Ewing rented space. Later, the Patent Office building, with a new east wing, provided permanent space in 1852. Ewing initiated the Interior Department's culture of corruption by wholesale replacement of officials with political patronage. Newspapers called him "Butcher Ewing" for his efforts.

In 1850 Ewing was appointed to the Senate to fill the vacancy created by the resignation of Thomas Corwin, and served from July 20, 1850-March 3, 1851. Ewing was unsuccessful in seeking re-election in 1851. Ewing was appointed by President Andrew Johnson to a third post as Secretary of War in 1868 following the firing of Edwin Stanton but the Senate, still outraged at Johnson's firing of Stanton - which had provoked Johnson's impeachment - refused to act on the nomination.

Ewing raised as a foster son the famous general William Tecumseh Sherman, who also married Ewing's daughter.