He graduated from Centre College in Danville, Kentucky in 1840 and resided in Washington, DC during his father's tenure as Postmaster General in the Tyler Administration.

In 1846, the Wickliffes moved to St. Francisville, Louisiana so Robert could recover from pneumonia at his wife's family's plantation, Wyoming.

Reelected in 1853, he is appointed Chairman of the Commission on Public Education, and became President Pro Tempore of the Louisiana Senate when W. W. Farmer became Lieutenant Governor.

In his inaugural address in Baton Rouge, Governor Wickliffe advocated a united Democratic South to protect state's rights and he championed the expansion of American power to the Caribbean, Mexico, Cuba and Central America in order to protect slavery in the United States.

The unrest changed to violence in New Orleans, which was under Know Nothing control, and Wickliffe was forced to dispatch the militia to ensure the validity of the 1858 elections.

In 1892, he reentered electoral politics when he was nominated for Lieutenant Governor by the Louisiana Lottery faction of the Democratic Party.