In 1831, Pike left Massachusetts to travel west, first stopping in St. Louis and later moving on to Independence, Missouri. At Independence, he joined an expedition to Taos, New Mexico. During the excursion his horse broke and ran, forcing Pike to walk the remaining 500 miles to Taos. After this he joined another expedition to New Mexico and Texas. After traveling about 1300 miles - 650 on foot - he finally arrived at Fort Smith, Arkansas.

Settling in Arkansas in 1833, he taught school, managed and owned a newspaper and rose politically in the Whig Party. He married Mary Ann Hamilton in 1834, and to their union was born six children. He then began to study law and was admitted to the bar in 1837. Pike became the first reporter for the Arkansas Supreme Court. He became a champion for the Native Americans and a voice for women's rights. One of his passions was poetry, which he wrote all of his life. His poems were highly regarded in his day, but are now mostly forgotten.

When the Mexican-American War (1846-1848) began, Pike led his Arkansas volunteer cavalry, serving in the Battle of Buena Vista. He and his commander, John S. Roane, had strong differences of opinion. This situation led later to a duel between Pike and Roane on the Arkansas River just after the war. The duel ended with nobody injured, which became known as the last duel in Arkansas. Pike returned to the practice of law, moving to New Orleans for a time beginning in 1853. He returned to Arkansas in 1857 and became a member of the Know-Nothing party. By this time he had become famous as the "Plato of America."

Before the War Between the State (1861-1865), he was firmly against secession. However, when the war started he nevertheless took the side of the Confederacy. Pike was commissioned as a brigadier general in 1861, and given a command in the Indian Territory. In this capacity he negotiated several treaties and led the Indians at the Battle of Pea ridge Arkansas.

Pike's real interest was in Freemasonry and after the war he resumed his activities in the fraternity, especially the Scottish Rite. He was the Sovereign Grand Commander of the Scottish Rite's southern Jurisdiction from 1859 until his death, a total of thirty-two years. He devoted a large amount of his time to developing the rituals of the order.

Pike is still regarded in America as an eminent and influential Freemason. He is the only Confederate military officer or figure to be honored with an outdoor statue in Washington, D.C. - Judiciary Square.