At the outbreak of the Mexican War Roane was made a Lieutenant Colonel in Archibald Yell's Arkansas infantry regiment and graduated to command of the regiment when Colonel Yell was mortally wounded repelling the charge of the Mexican lancers at the Battle of Buena Vista. He was officially appointed to Colonel of the regiment on 28 February 1847.
Roane was known to be jealous of the honor of his state and once challenged Albert Pike to a duel over, what he perceived as, derogatory statements made by Pike about the Arkansas regiment in the Mexican War. The duel was fought but neither combatant was injured.
After most troops were moved from Arkansas across the Mississippi River Roane was placed in charge of the defense of Arkansas. At this time the state was nearly defenseless and Roane, with the newly appointed commander of the Trans-Mississippi District General Thomas C. Hindman, cobbled together a reasonable defensive force.
General Roane and his brigade took part in numerous battles in the Trans-Mississippi District including the Battle of Prairie Grove in northwest Arkansas.
John Selden Roane died in Pine Bluff, Arkansas.
John Selden Roane is buried at Oaklawn Cemetery in Little Rock, Arkansas.