He served as military officer in the United States Army during several wars, accompanied John C. Frémont on his second expedition through the West, and was instrumental in the formation of the government of the Oregon Territory.

As a politician and writer, he was an inveterate believer in Manifest Destiny and was a visionary booster of new settlement to the West, helping lay the groundwork in his writings for a modern theory of the succession of civilizations.

His administration was consumed largely with the defense of the new territory in the early days of the American Civil War and was brought down after only one year by scandalous financial dealings.

After the demise of his political career, he made a large fortune as a land speculator in New Mexico, although his dealings were questionable and possibly illegal.

In 1846, during the Mexican–American War, he was commissioned as Major of the 1st Missouri Mounted Infantry Regiment and marched to Chihuahua City in the successful bloodless campaign to capture New Mexico.

He was considered to have served with distinction in the campaign and was later given command of a mounted infantry battalion to protect the Santa Fe Trail against attacks by Native Americans.

In the book he predicted that the Mississippi River valley would become the center of western civilization with the new settlement of Denver as its capital, based partly on its location near the 40th parallel north.

[citation needed] Throughout his career in politics, Gilpin was a strong believer that the American West would not only be settled but also eventually hold an enormous population.

This theory held that settlement in the arid lands of the West would actually increase rainfall in the region, making it as fertile and green as the Eastern United States.

His selection over the local favorite William Larimer came as a surprise to many, and was motivated in part by the fact that Gilpin was backed by the Governor of Missouri, a slave state that Lincoln was eager to keep in the Union.

The movement against him was fostered by the anger of William N. Byers, the powerful editor of the Rocky Mountain News, whose newspaper had been bypassed in favor of a rival in the awarding of the territorial printing contract.

The 1st Colorado Volunteers played a critical role in repelling the Confederates, routing the Texans at the Battle of Glorieta Pass, which became known as the "Gettysburg of the West".

Despite the enormous success of the regiment, the territory was mired in financial problems caused by Gilpin's drafts, which had tied up most of the circulating currency without any resolution regarding their validation.