Brown's Kentucky family were slaveowners, but he endorsed gradual emancipation and the colonization of freed slaves to Africa. Brown joined the anti-slavery Democratic faction of Senator Thomas Hart Benton of Missouri. In 1852, Brown and Frank Blair bought a St. Louis newspaper (the Morning Signal), which they renamed the Missouri Democrat. Brown contributed commentary to the journal, including voicing his free-soil opposition to the expansion of slavery. In 1854, he became the paper's editor in chief.

Brown entered electoral politics in 1852 when, backed by the antislavery German community in St. Louis, he won a seat in the state legislature. A gunshot to the knee in an 1856 duel with Thomas Reynolds, the leader of Missouri's pro-slavery Democrats, left Brown with a permanent limp (Reynolds was unharmed). During his tenure in the state legislature, Brown consistently took a firm free-soil stance, and continued to advocate gradual emancipation and colonization. In 1858, he was defeated for reelection, and was pressured by Frank Blair, for unclear reasons, to resign from the Missouri Democrat. The next year, Brown established St. Louis's first streetcar railroad company.

In 1860, Brown joined the Republican party and attended the national convention in Chicago as a delegate-at-large. He dutifully endorsed Edward Bates, Missouri's favorite-son candidate, before switching enthusiastically to the eventual nominee, Abraham Lincoln of Illinois. When the Civil War began, Brown became colonel of a regiment of 90-day volunteers. They saw no action, and he did not reenlist. In August 1861, Brown strongly supported General John C. Frémont's emancipation order in Missouri (nullified by President Lincoln). Brown resumed editorship of the Missouri Democrat, using its pages to encourage immediate emancipation.

Republicans nominated Brown for the U.S. Senate in 1862, but no candidate was able to secure a majority in the divided state legislature. Over the next year, he helped found the Radical Union party in Missouri on a platform promoting immediate emancipation. In December 1863, Radical Unionists in the state legislature were finally numerous enough to elect Brown to a truncated four-year term in the U.S. Senate. In 1864, he and other Radicals backed General Frémont's challenge to President Lincoln's reelection. When Frémont withdrew in October, Brown supported the president.

Brown did not seek reelection to the Senate in 1866, citing ill health. He continued to be active in politics, however, calling for a convention of Missouri Radicals to endorse the policies of universal suffrage (i.e., voting rights for black men) and universal amnesty (i.e., pardons for all former Confederates). In 1870, Brown was elected governor of Missouri on a Liberal Republican platform of universal suffrage (including for women), universal amnesty, civil service reform, lower tariffs, and an eight-hour day. Democrats also endorsed his candidacy, thus providing a blueprint for the national Liberal Republican-Democratic coalition two years later.

In 1872, Liberals unhappy with the administration of President Ulysses S. Grant bolted the Republican party to hold their own Liberal Republican convention in Cincinnati. New York Tribune editor Horace Greeley was nominated unexpectedly for president, and Brown, who had surprised colleagues by endorsing the controversial editor, was nominated for vice president. The next month, the Democratic party also nominated the Greeley-Brown ticket and accepted the Liberal Republican platform. During the campaign, Brown was ridiculed by cartoonist Thomas Nast as the tag on Greeley's coattail. After their defeat in the November election, Brown returned to the practice of law, and did not participate in politics except as an observer at the Democratic National Convention in 1876. He died in St. Louis in 1885.

Source consulted: American National Biography.