In 1850, he was elected to Congress as a Whig, defeating future Civil War general Winfield S. Featherston. Two years later, Wilcox was defeated for re-election. In 1853, he moved to San Antonio, Texas, and resumed his law practice. He briefly dabbled in the Know Nothing political movement, serving as a presidential elector in 1856, but then joined the Democratic Party in 1858, attending the National Convention that year.
With talk of secession increasing in Texas, Wilcox, a strong supporter of states rights, was selected as a delegate to the state's Secession Convention in 1861. He served on the committee that drafted the ordinance of secession. He was elected to the First Confederate Congress in November 1861 and traveled to Richmond, Virginia to assume his duties, serving on various committees and proving to be a staunch support of the policies of PresidentJefferson Davis. He was active in helping raise recruits and organizing the Texas Brigade.