McCoy, his son John, his daughter Delilah and her missionary husband Johnston Lykins, worked together as missionaries to the Shawnee and Lenape (Delaware), following them to what is now Kansas City, Missouri, on the border of Indian Territory and near their reservations.
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The Carey Mission, as he named it, was 100 miles from the nearest White settlement.
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McCoy founded his first "religious station" and school in October 1818 in what became Parke County, Indiana, on Big Raccoon Creek upstream from the later Wea Indian reservation at Armiesburg.
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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.
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He became involved with the work being performed among the area's American Indian tribes by Isaac McCoy, joining the McCoy mission to the Wea peoples in northern Indiana in 1819.