After his admission to the Kentucky bar in Lexington, he went on to practice in St. Louis in 1842 with his elder brother; in 1842–1845, he worked in the law office of Thomas Hart Benton.

In collaboration with Alexander William Doniphan, Willard Preble Hall, and David Waldo, Blair developed an American Code of Law for the region and became a judge of the newly established circuit court.

On January 14, 1858, he delivered a major speech describing slavery as a national problem, proposing to solve it by both gradual emancipation and the settling of freed slaves in Latin and Central America.

However, he resigned just seventeen days later on June 25, then lost his bid in the subsequent special election, the seat instead being refilled by Barret on December 3.

In 1862, he won election to the 38th Congress but in a reversal of fortune was himself forced to relinquish his seat on June 10, 1864, after his opponent, Samuel Knox, successfully contested the results.

[11] The Blairs were unwavering supporters of Abraham Lincoln during his rise to the presidency and years in office and in return enjoyed his political patronage.

Immediately after South Carolina's secession in December 1860, Blair, believing that the southern leaders were planning to carry Missouri into the movement, began active efforts to prevent it.

[13] He personally organized and equipped a force of several thousand strong Home Guard, drawn from the Wide Awakes, the Republican marching clubs of the 1860 presidential campaign, and the members of the German gymnastic movement in St. Louis, Turnverein.

When tensions rose, Blair and Captain (later brigadier general) Nathaniel Lyon suddenly transferred the arms in the U.S. Arsenal at St. Louis to Alton, Illinois.

[14] On May 10, 1861, Lyon, with the Home Guards and a U.S. regular Army company, captured several hundred secessionist state militia which had been positioned to seize the Arsenal.

The Camp Jackson Affair gave the Federal cause a decisive initial advantage in Missouri but also inflamed secessionist sentiments in the state.

Lyon drove Jackson and Price to the southwestern corner of Missouri before he was killed at the Battle of Wilson's Creek, while Blair helped organize a new all-Unionist state government, and John C. Frémont took over as the U.S. Army Western Department commander.

[17] The election was contested, but in the end, Blair was defeated after the Missouri Attorney General Robert Franklin Wingate ruled that votes cast after sundown were valid.

[13] Blair contributed to the Democratic defeat by going on a speaking tour in which he framed the contest with Ulysses S. Grant and the pro-Reconstruction Republicans in stark racial terms, warning of the rule of "a semi-barbarous race of blacks who are worshipers of fetishes and poligamists" and wanted to "subject the white women to their unbridled lust.

Blair's consuming interest in politics kept him active and he served as Missouri's state superintendent of insurance until his death from head injuries after a fall on July 8, 1875, at the age of 54.

[22] William T. Sherman after hearing about Blair's death said, "I always regarded him as one of the truest patriots, most honest and honorable men, and one of the most courageous soldiers this country ever produced.

"[23] Ulysses S. Grant wrote about Frank Blair in his memoir that, "There was no man braver than he, nor was there any who obeyed all orders of his superior in rank with more unquestioning alacrity.

In 1899, the state of Missouri donated a marble statue of Blair by Alexander Doyle to the U.S. Capitol's National Statuary Hall Collection.