It formed part of the north–south chain of forts that was intended to maintain peace on the frontier of the American West and to protect the southwestern border of the Louisiana Purchase.

The post surgeon began taking meteorological observations in 1824, and the fort provided the earliest known weather records in Oklahoma.

They also settled strife between the indigenous Osage Nation, which had been in the area since the seventeenth century, and the earliest bands of western Cherokee settlers.

The American author Washington Irving accompanied troops exploring the southern Plains west of Fort Gibson in 1832.

This excursion and another journey in 1833 both failed to find any significant nomadic Indian tribes, but Washington Irving wrote A Tour of the Prairies in 1835 from his experiences.

General Henry Leavenworth in 1834 led the First Dragoon Expedition on a peace mission to the west, and finally established contact with the nomadic Indian tribes.

A West Point officer assigned to the fort said the men felt that expeditions to the Plains in the 1830s were "a veritable death sentence.

"[4] During these years, the soldiers at Fort Gibson built roads, provisioned incoming American Indians removed from the eastern states, and worked to maintain peace among antagonistic tribes and factions, including the Osage Nation, who settled the region in the 18th century,[5] and the Cherokee Nation, a people forcibly removed from the American South to the Indian Territory.

Their absence weakened the military power and pacification capacity at Fort Gibson, but the reduced garrison maintained stability in the region.

Notable American soldiers stationed at (or at least visiting) Fort Gibson include Stephen W. Kearny, Robert E. Lee, and Zachary Taylor.

The Army stationed Jefferson Davis, later president of the Confederate States of America, and more than 100 other West Point cadets at the fort.

Colonel Arbuckle tried to prevent intratribal strife within the Cherokee, but Chief John Ross and his followers refused to acknowledge the government that earlier "Old Settlers" had established in Indian Territory.

Its troops under General Blunt marched southward in July 1863 and won the Battle of Honey Springs, the most important in Indian Territory.

[4] In the summer of 1864, the steamboat J.R. Williams came up the Arkansas River with a thousand barrels of flour and 15 tons of bacon to resupply Union troops at Fort Gibson.

Soon after, workers were sent to the area to build the Missouri–Kansas–Texas Railroad from Baxter Springs, the first "cow town," in Kansas, to the Red River crossing at Colbert's Ferry, Indian Territory, along the Texas border.

The Kansas and Arkansas Valley Railway built track through the area in 1888, and the town of Fort Gibson, Oklahoma began to develop.