He was an advocate of saving the dwindling tribes from decades of ongoing American abuse, by leading their charitable removal from the eastern United States into their own homesteading.

He serially established successful tribal missions at the remote western American frontiers, hundreds of miles beyond any white settlements, repeatedly relocating westward due to encroachment and exploitation.

He wrote books and made many trips to Washington, D.C. to solicit funds, create programs, and propose a permanent sovereign tribal colony within Indian Territory, which instead became the states of Kansas, Nebraska, and Oklahoma.

[7]: 4–15 [8] McCoy founded his first "religious station" and school in October 1818 in what became Parke County, Indiana, on Big Raccoon Creek[1] upstream from the later Wea Indian reservation at Armiesburg.

In February 1819, he performed the first marriage in the county, between two métis, Christmas Dazney (Noel Dagenet) and Mary Ann Isaacs, a Brotherton or Mohegan from upstate New York.

His school at Fort Wayne attracted 40 Miami, Potawatomi, and mixed-blood children, several whites, and one African American.

In 1821, McCoy made the first of many visits to Washington, DC, seeking approval by the federal government, unsuccessfully on this occasion, for him to appoint teachers, blacksmiths, and other "agents of civilization" to be provided the Indians under newly ratified treaties.

[7]: 56–58  In 1821, Chief Little Turtle of the Miami, along with 16 other Indians and the captive William Wells, also traveled to Washington, DC seeking aid.

The Pottawatomi gave McCoy a relatively warm welcome and helped feed his large family and Indian students through their early seasons in the hostile territory.

McCoy once wrote, "Blessed be God, we have not yet suffered for lack of food; for parched corn is an excellent substitute for bread.

"[11]: 86 In 1826, McCoy moved his family deeper into the western frontier, where he established the Thomas Mission to the Odawa people, at what later became Grand Rapids, Michigan.

[1] He believed that getting the tribes to their own, isolated places, away from the reach of whiskey traders and others who were exploiting them, would give them a better chance of surviving and becoming Christianized.

[7]: 67–70  McCoy expanded his concept later to propose the creation of an Indian state making up most of the land area of what is now Kansas, Oklahoma, and Nebraska.

They never accomplished more than "to soften the pillows of the dying" and had "too recently been transplanted from the sterile plains of religious bigotry, to expand with liberal views of the character, and of the just rights of man".

Rather, he placed his faith in the government to create for the Indians "a country of their own" where they could "feel their importance, where they can hope to enjoy, unmolested, the fruits of their labours, and their national recovery need not be doubted".

During the tragic removals forced on the Indians by the U.S. government in the 1830s and later, thousands died of neglect and arrived in Kansas and Oklahoma impoverished and starving.

The possibility of removing eastern Indians west of the Mississippi River was enhanced in 1825 when the Osage and the Kaw ceded large portions of their lands in Kansas and Oklahoma to the United States.

In 1828, Congress authorized McCoy to lead an expedition to survey lands to which the Chickasaw, Choctaw, and Creek of the Southeast could be relocated.

In 1830, with Kaw "mixed blood" Joseph James as his guide, he surveyed and established the boundaries of a reservation for the Delaware tribe who were persuaded to move there from their territories in southern Missouri.

He laments the callous conquest of the native tribes, the disregard of their very concept of government, land rights, and freely chosen lifestyle.

He compares this to a hypothetical conquest of the modern Washington, DC by Chinese invaders who could similarly see America as alien, uncivilized, and inferior.

Or, visit the Indians in their tents, and they will tell you themselves, and that too, in expressions of grief and despair, that, unless your heart be cased in adamant, will make you both sigh and weep.

For the next ten years, McCoy was engaged in surveying boundaries of reservations for more than twenty tribes who moved west to present-day Kansas.

In 1833, McCoy was reportedly armed and involved with a company of "ruffians", a mob in Independence, Missouri who attacked Mormon families at gunpoint and expelled them from their homes onto the prairie, where they nearly starved.

Isaac McCoy (a noted Baptist missionary to the tribes), with gun in hand, ordering the people to leave their homes immediately and surrender everything in the shape of arms.

Other pretended preachers of the Gospel took part in the persecution - speaking of the [Mormon] Church as the common enemies of mankind, and exulting in their afflictions.

"[16] Although he was involved in numerous projects on behalf of what he perceived as the best interest of Indians, McCoy was nearly destitute during much of the 1830s, taking in boarders and working as bookkeeper in a neighboring store.

[11]: 94 In 1840, McCoy wrote one of the earliest, most personally informed reports on the Midwestern Native American tribes, The History of Baptist Indian Missions.