Continuity with The Last of the Mohicans is indicated by the appearance of the grandson of Duncan and Alice Heyward, as well as the noble Pawnee chief Hard Heart, whose name is English for the French nickname for the Delaware, le Coeur-dur.

The story opens with Ishmael, his family, Ellen and Abiram slowly making their way across the virgin prairies of the Midwest looking for a homestead, just two years after the Louisiana Purchase, and during the time of the Lewis and Clark Expedition.

They meet the trapper (Natty Bumppo), who has left his home in New York State to find a place where he cannot hear the sound of people cutting down the forests.

In the years between his other adventures and this novel, he tells us only that he has walked all the way to the Pacific Ocean and seen all the land between the coasts (a heroic feat, considering Lewis and Clark hadn't yet completed the same trek).

The trapper helps the family relocate their wagons, including one with mysterious contents, to a nearby butte where they will be safer when the Tetons return.

The trapper, Paul, and Middleton return to camp, find Inez whom Abiram and Ishmael had been keeping captive, and flee with her and Ellen.

They meet up with Hard-heart, a Pawnee Indian who survived the fire wrapped in a buffalo skin, and attempt to escape to his village.

Middleton, Inez, Paul, and Ellen travel back to Louisiana and Kentucky, respectively, while the trapper joins a Pawnee village located on a tributary of the Missouri River.

In the spirit of Daniel Boone, who is said to have thought "a population of ten to the square mile inconveniently crowded,"[1] The Prairie incorporates the historical phenomenon of the migration of settlers into the territories of the Louisiana Purchase.

When James was 14 months old, his father moved the family to a vast tract of wilderness at the headwaters of the Susquehanna River in New York State where, on a system of small land grants, he had established the village of Cooperstown at the foot of Otsego Lake.