Tyler was a Southerner to his core, and was highly loyal to Virginia. He developed his political career around the narrow interests of the Southern slave-owning planters who also valued states' rights. He was a slave owner himself (he had about 70 slaves) and opposed efforts to open political participation to men without property.

Representing Virginia in the U.S. House of Representatives, Tyler opposed the Missouri Compromise of 1820, which allowed Missouri to be admitted as a slave state only if Maine were admitted as a free state. Tyler opposed placing geographical restrictions on the spread of slavery, seeing them as an abuse of federal power. Afterward, he resigned in discouragement from the House. He once said that "the Southern states are in constant apprehension [anxiety about the future] lest the national government should be converted into a mere majority machine."