Knox was a candidate for the U.S. House of Representatives from Missouri's 1st congressional district in 1862 against incumbent Republican Francis P. Blair Jr..

The campaign revolved around competing proposals for the abolition of slavery in Missouri, with Blair endorsing a plan for gradual compensated emancipation backed by Governor Hamilton Rowan Gamble, leader of the state's conservative Unionists.

This conformed to the moderate position occupied by President Abraham Lincoln in the summer of 1862, but disappointed radical Unionists, including many of Blair's German-American supporters, who favored immediate emancipation.

The election was chaotic and closely contested, with success hinging on the votes of active service Union soldiers.

Blair led early in the count and was seated at the start of the 38th Congress, but his plurality was reversed by late returns favoring Knox; the latter successfully challenged the certified result and replaced Blair on June 10, 1864, serving until the expiration of his term on March 4, 1865.