Though St. Vrain spent much time traveling and at Bent’s Fort, he also maintained a home and multiple business interests in Taos, New Mexico. St. Vrain ran the company stores in Taos and Santa Fe and served as American consul in Santa Fe during the 1830's.
Both St. Vrain and the Bent brothers became very influential as they were highly regarded for their business acumen and gentlemanly ways, and during these influential times, made occasional trips to Washington D.C.

In 1844, he also partnered with Cornelio Vigil, a prominent Taos trader and former mayor of Taos, in procuring the Vigil-St. Vrain Land Grant, which encompassed some 4 million acres spread across south-eastern Colorado. However, after the American takeover of the southwest, this led to all types of legal difficulties with the Mexican-American War impending this led to legal difficulties, which ultimately led to the grant being decreased to 97,000 acres.

With the Mexican-American War impending, St. Vrain and Charles Bent rushed to Missouri, on their way stopping at Fort Leavenworth, Kansas where Colonel Stephen W. Kearny was stationed. During their visit, they supplied the army with information about New Mexico territory and its influential people.

During the Mexican-American War, the Taos Revolt began on January 19, 1847 and lasted through July. The insurrection was against the American occupation of present-day northern New Mexico. Taos citizens along with the help of their Pueblo, Apache, Comanche and Kiowa Indian allies, rose up against the Americans. During this time, St. Vrain organized a force at Santa Fe, New Mexico to put down the Taos insurrection. Raising some 65 volunteers, they joined more than 300 U.S. troops in Santa Fe and set off for Taos. Along the way, they forced the retreat of some 1,500 Mexican and Indian rebels, who took refuge in a thick-walled adobe church in Taos Pueblo. During the Siege of Pueblo de Taos, St. Vrain's "Emergency Brigade" positioned themselves between the church and the mountains, cutting off the forces attempting to escape the federal troops' frontal assault. The mounted volunteers reportedly raided the rebels and killed 51 Mexicans, Taos Indians, and Apache Indians in the fierce, close-quarter fighting that followed. St. Vrain was nearly killed in the battle but was saved by a man named Manuel Chaves. In the end, the rebellion was crushed.

In the meantime, his partner, Charles Bent, who had become the first Governor of the newly acquired New Mexico Territory, was scalped alive and killed in his home on January 19, 1847.