Following the collapse of the Whig Party in the mid-1850s, Etheridge, like many Tennessee Whigs, joined the nativist American ("Know Nothing") Party. Assailed for his vote against the Kansas-Nebraska Act, he was nearly defeated for reelection in 1855, edging his Democratic challenger, Thomas J. Freeman, by just over 500 votes with more than 15,000 cast. Etheridge was the only Southern representative to support an 1857 House resolution condemning the repeal of the Missouri Compromise. In February 1857, Etheridge spoke in opposition to the reopening of the African slave trade, calling any such proposition "shocking to the moral sentiment of the enlightened portion of mankind."