In 1831 Pike left Massachusetts to travel west, first stopping in St. Louis and later moving on to Independence, Missouri. In Independence, he joined an expedition to Taos, New Mexico, hunting and trading. During the excursion his horse broke and ran, forcing Pike to walk the remaining 500 miles to Taos. After this he joined a trapping expedition to the Llano Estacado in New Mexico and Texas. Trapping was minimal, and after traveling about 1300 miles (650 on foot), he finally arrived at Fort Smith, Arkansas.
Settling in Arkansas in 1833, he taught school and wrote a series of articles for the Little Rock Arkansas Advocate under the pen name of "Casca." The articles were popular enough that he was asked to join the staff of the newspaper. Later, after marrying Mary Ann Hamilton, he purchased part of the newspaper with the dowry. By 1835 he was the Advocate's sole owner. Under Pike's administration the Advocate promoted the viewpoint of the Whig party in a politically volatile and divided Arkansas.
He then began to study law, and was admitted to the bar in 1837, selling the Advocate the same year. He was the first reporter for the Arkansas supreme court, and also wrote a book (published anonymously), titled The Arkansas Form Book, which was a guidebook for lawyers.
After the war, Pike returned to the practice of law, moving to New Orleans for a time beginning in 1853. He wrote another book, Maxims of the Roman Law and some of the Ancient French Law, as Expounded and Applied in Doctrine and Jurisprudence. Although unpublished, this book increased his reputation among his associates in law. He returned to Arkansas in 1857, gaining some amount of prominence in the legal field and becoming an advocate of slavery, although retaining his affiliation with the Whig party. When that party dissolved, he became a member of the Know-Nothing party. Before the Civil War he was firmly against secession, but when the war started he nevertheless took the side of the Confederacy.
He also made several contacts among the Native American tribes in the area, at one point negotiating an $800,000 settlement between the Creeks and other tribes and the federal government. This relationship was to influence the course of his Civil War service. At the beginning of the war, Pike was appointed as Confederate envoy to the Native Americans. In this capacity he negotiated several treaties, one of the most important being with Cherokee chief John Ross, which was concluded in 1861.
Pike was commissioned as a brigadier general on November 22, 1861, and given a command in the Indian Territory. With Gen. Ben McCullough, Pike trained three Confederate regiments of Indian cavalry, most of whom belonged to the "civilized tribes", whose loyalty to the Confederacy was variable. Although victorious at the Battle of Pea Ridge (Elkhorn Tavern) in March, Pike's unit was defeated later in a counterattack, after falling into disarray. Also, as in the previous war, Pike came into conflict with his superior officers, at one point drafting a letter to Jefferson Davis complaining about his direct superior.
After Pea Ridge, Pike was faced with charges that his troops had scalped soldiers in the field. Maj. Gen. Thomas C. Hindman also charged Pike with mishandling of money and material, ordering his arrest. Both these charges were later found to be considerably lacking in evidence; nevertheless Pike, facing arrest, escaped into the hills of Arkansas, sending his resignation from the Confederate Army on July 12. He was at length arrested on November 3 under charges of insubordination and treason, and held briefly in Warren, Texas, but his resignation was accepted on November 11 and he was allowed to return to Arkansas.
He had in the interim joined a Masonic lodge and become extremely active in the affairs of the organization, being elected Sovereign Grand Commander of the Scottish Rite's Southern Jurisdiction in 1859. He remained Sovereign Grand Commander for the remainder of his life (a total of thirty-two years), devoting a large amount of his time to developing the rituals of the order. Notably, he published a book called Morals and Dogma of the Ancient and Accepted Scottish Rite of Freemasonry in 1871, of which there were several subsequent editions.
Pike is still sometimes regarded in America as an eminent and influential Freemason.
Additionally, Pike wrote on several legal subjects, and continued producing poetry, a hobby he had begun in his youth in Massachusetts. His poems were highly regarded in his day, but are now mostly forgotten. Several volumes of his works were self-published posthumously by his daughter.
In 1859 he received an honorary Ph.D. from Harvard but declined it ("The Phoenix," Manly P. Hall).
Pike died in Washington, D.C., aged 81, and was buried at Oak Hill Cemetery (against his wishes—he had left instructions for his body to be cremated).
In 1944 his remains were moved to the House of the Temple, headquarters of the Southern Jurisdiction of the Scottish Rite.