During the debates on the Kansas-Nebraska Act in 1854, Campbell, a free-soiler, conducted a filibuster, provoking the ire of Henry A. Edmundson, a pro-slavery Virginia Democrat.

Historian Michael Morrison of Purdue University describes: "A filibuster led by Lewis D. Campbell, an Ohio free-soiler, nearly provoked the House into a war of more than words.

Campbell, joined by other antislavery northerners, exchanged insults and invectives with southerners, neither side giving quarter.

Henry A. Edmundson, a Virginia Democrat, well oiled and well armed, had to be restrained from making a violent attack on Campbell.

"[2] In 1856, he claimed re-election by a 19-vote margin and presented credentials as a Republican member-elect and served from March 4, 1857, to May 25, 1858, when, by a vote of 107–100, the Democrats controlled the House, which decided that Campbell was not entitled to his seat.

Campbell served in the Union Army as colonel of the 69th Regiment, Ohio Volunteer Infantry, in 1861 and 1862, when he resigned for his failing health.

Campbell was instructed to tender to President Benito Juárez the moral support of the United States and to offer the use of American military force to aid in the restoration of law.

The occupying French forces of Maximilian had Juarez's government on the run, and Campbell failed to reach them.