Retiring to his Silver Spring, Maryland, country estate, Blair remained highly influential through his reputation and friendships. In 1848, although he owned a few slaves, he strongly supported Van Buren's Free Soil presidential candidacy. Blair was certain that slavery could not spread to the territories taken from Mexico and believed that southern radicals were misrepresenting the issue to promote disunion. In 1852 he wrote pamphlets supporting the Democratic candidacy of Franklin Pierce but was bitterly disappointed in him when Pierce promoted the Kansas-Nebraska Act, which repealed the Missouri Compromise and opened the western territories legally to slavery. Blair helped organize the new Republican party against slavery in Kansas, and when abolitionist senator Charles Sumner was caned by a congressman from South Carolina, Blair brought him to Silver Spring for recuperation. In 1856 Blair chaired the first Republican National Convention and later was instrumental in securing the nomination of John C. Frémont for president. In a widely distributed pamphlet published in April of that year, A Voice from the Grave of Jackson
, Blair worked to convert northwestern Democrats by arguing that Jackson, if alive, would be a Republican.
In Dred Scott v. Sandford (1857), Blair's son Montgomery Blair argued for the plaintiff's freedom, and another son, Frank (Francis Preston Blair, Jr.), a congressman from Missouri, made eloquent speeches advocating abolition and deportation of the freed slaves to Latin America. Blair and his sons were influential delegates at the 1860 Republican convention and were rewarded when Abraham Lincoln appointed Montgomery Blair postmaster general. Throughout Lincoln's presidency, Preston Blair and his son Frank were close friends and confidantes.