The poem starts by telling us how the Master of Life, Gitche Manito, came down from the skies and told all the people of the Earth to stop fighting and get along. To seal the deal, he had these people make peace pipes, which they take out and smoke together whenever a conflict arises. Then Gitche Manito throws in an added bonus: he tells the people that he will soon send a prophet who will suffer on their behalf so that they will all live better lives.
Some time after Gitche Manito's appearance, a boy named Hiawatha is born to a woman named Wenonah. Hiawatha's father is a demigod who controls the west wind, but as a dad he's a deadbeat. He deserts Hiawatha's mother, who ends up dying from heartbreak. In the meantime, Hiawatha grows up to be a strong and wise young man whose great reputation travels all across the land.
The book goes on to tell us about all the great stuff Hiawatha does, like making the corn grow better and killing a giant fish-god named Mishe-Nahma. Eventually, Hiawatha gets lonely and decides to ask a woman named Minnehaha to marry him. She says yes and they live happily together. Along the way, Hiawatha finds the time to invent reading and writing and to teach these things to his people.
In the second half of the poem, Hiawatha loses his two best friends. Then he has to chase down a troublemaker named Pau-Puk-Keewis who has been destroying everything in his path. Finally, a terrible winter kills Hiawatha's wife Minnehaha with a fever. Hiawatha feels as though there's nothing left in his life to keep him in his village. One night, he has visions of white men arriving in a giant boat and teaching his people a new religion. Sure enough, this vision comes true and Hiawatha trusts that his people will be safe with the whites (um, he might be mistaken on that one).
At the end of the poem, Hiawatha gets in his canoe and paddles away from his village. He doesn't know when or if he'll ever come back. And that's that.