Pugh served a single term in the United States Senate from 1855 to 1861, losing a re-election bid to Salmon P. Chase, whom he had replaced.

Pugh explained, "This is the first time I ever heard, in a case where nine judges pronounce their opinions seriatim, that because one of them {Roger B. Taney} in illustration collaterally makes a reference, that becomes the decision of the court."

[5] Despite his loss to Republican Salmon P. Chase in his attempt to secure a second term to the Senate in 1860, Pugh would continue to vocally politically during his remaining time in office.

Most notably, during the secession crisis following the election of Abraham Lincoln to the presidency, Pugh would be one of the most vocal voices in Congress in arguing against the use of coercion to force the seceding Southern states back into the Union.

During the Civil War, he fell into disfavor with the citizens of Ohio because he was a Democrat and for defending Vallandigham and later in 1863, he lost the election for the office of Lieutenant Governor.

He emerged to the political front again in 1873 when he was elected to become a delegate to the Ohio State Constitutional Convention but withdrew from the deliberations and declined to serve.