Wilmot modeled the language for what would usually be referred to as the Wilmot Proviso after the North West Ordinance of 1787. Although known as the Wilmot Proviso, it originated with Jacob Brinkerhoff of Ohio, Wilmot being selected to present it only because his party standing was more regular. The House, after first voting down a counter-proposal simply to extend the Missouri Compromise line across the Mexican Cession, passed the proviso by a vote of 83–64. This led to an attempt to table the entire appropriations bill rather than pass it with "the obnoxious proviso attached", but this effort was defeated "in an ominously sectional vote, 78–94". The Senate adjourned rather than approve the bill with the proviso.

David Wilmot was born in Bethany, Pennsylvania, to Randall (1792–1876) and Mary (née Grant) Wilmot (1792–1820). His father was a well-to-do merchant, and David's early life was a comfortable one. He was educated at the local Beech Woods Academy and later at the Cayuga Lake Academy in Aurora, New York. Moving to Wilkes-Barre in 1832, he read law under George W. Woodward and was admitted to the bar in Bradford County, Pennsylvania, in August 1834.

In 1836 he married Anna Morgan. The couple had three children, none of whom survived childhood.

Wilmot was elected Representative from Pennsylvania's 12th congressional district as a Democrat in 1844. He served from 1845 until 1851, in the 29th, 30th and 31st Congresses. He initially supported the policies of President James Polk. Also, as a Representative of a largely agrarian district, he voted for the Walker Tariff of 1846, which made a moderate reduction in tariff rates. Only gradually did Wilmot come to believe that the South was dominating the national government to the detriment of the rest of the nation.

Although Wilmot opposed the extension of slavery into the territories, he supported Polk in the initiation of the Mexican-American War, and was still considered a Democratic Party loyalist. But on August 8, 1846, an appropriations bill for $2 million to be used by the President in negotiating a treaty of peace with Mexico was introduced in the House of Representatives.

By 1848 Wilmot was thoroughly identified as a Free Soiler, but, like many other Free Soilers, he did not oppose the expansion of slavery based on a legal rejection of the short-term existence of the institution itself. In a speech in the House, Wilmot said, "I plead the cause and the rights of white freemen [and] I would preserve to free white labor a fair country, a rich inheritance, where the sons of toil, of my own race and own color, can live without the disgrace which association with negro slavery brings upon free labor." Around the same time, however, Wilmot, in a New York speech, spoke of the ultimate demise of slavery when he argued, "Keep it within given limits …and in time it will wear itself out. Its existence can only be perpetuated by constant expansion. … Slavery has within itself the seeds of its own destruction."

Wilmot was presented as the Free Soil candidate for Speaker of the House in 1849 and was soon at odds with the mainstream Pennsylvania Democratic Party led by James Buchanan. Wilmot was forced to withdraw from the 1850 Congressional elections in favor of the more moderate Galusha A. Grow.

Wilmot was elected as a presiding judge of the 13th Judicial District of Pennsylvania in 1851, serving until 1861. He was instrumental in founding the Republican Party in Pennsylvania. He chaired the Republican Party platform committee, was a delegate to the 1856 national convention, and worked vigorously for the first Republican presidential candidate, John C. Fremont, in the 1856 election.

In 1857 Wilmot was the first Republican candidate for Governor of Pennsylvania, although he lost to william F. Packer. He was a delegate to the Republican National Convention in 1860 and was a key figure in obtaining the nomination for Abraham Lincoln. Wilmot was considered for a cabinet post by Lincoln, but he declined. In 1861 he was elected by the state legislature to the Senate to fill the seat of Simon Cameron. He served in that body from 1861 until 1863.

He was also a member of the peace convention of 1861, held in Washington, D.C., in an effort to devise means to prevent the impending American Civil War. Wilmot was appointed by President Abraham Lincoln as judge of the Court of Claims in 1863. He served until his death in Towanda in 1868. He is interred in Riverside Cemetery.

Wilmot was instrumental in establishing the Republican Party in Pennsylvania. His opposition to slavery did not include the evolving abolitionist position of immediately ending the institution in the entire country. His views on race were instead related to defense of white free labor and, by today’s standards, could be Classified as racist. He also served as a District Judge and on the US Court of Claims.