Tecumseh and the Quest for Indian Leadership is a biography focusing on the life of the title character, Tecumseh.

The main character is Tecumseh. He was chief of the Shawnee in the early nineteenth century. He sought to unite the Native American tribes west of the Appalachian mountains so that they could better withstand the increasing number of white settlers who were moving into their territory. Tecumseh hoped to mend long-standing divisions between the tribes so that they could act as a single, stronger unit. He campaigned hard to create this alliance, but it never became the universal Native American confederation that he hoped it would be. During the War of 1812, he allied himself with the British. He was killed in the Battle of the Thames in 1813, after which his Native alliance fell apart.

The book also deals heavily with Tecumseh's brother Tenskwatawa. Tenskwatawa became a religious figure in his time, frequently referred to as "The Prophet." Growing up, Tenskwatawa never seemed destined to amount to much. After partially blinding himself in an accident with a bow and arrow, Tenskwatawa descended into alcoholism. For much of his life, his family wanted nothing to do with him. After nearly dying from alcohol poisoning, Tenskwatawa had a spiritual epiphany. He started preaching that the Native peoples should unite to take back what had been taken by white settlers and began a revival of Native American religion. He urged his growing group of followers to give up the concept of property ownership introduced by white settlers. He became recognized as a spiritual leader and founded the settlement of Prophetstown. He joined up with Tecumseh in his mission to create a united Native alliance.

Tecumseh's father, Puckshinwa, was a minor chief among the Shawnee. He was killed by Americans at the Battle of Point Pleasant in 1774.

After his father's death, Chiksika, Tecumseh's older brother, took over the role of raising him.

The Shawnee warrior, Cornstalk (Hokoleskwa) serves as an introduction to the biography. He lived about a generation before Tecumseh's birth. Cornstalk fought against European settlement in his lands. He worked hard to keep his people neutral during conflicts between tribes and with the United States. He represented the Shawnee at peace councils conducted with the US government. He was murdered while in American custody in 1777, thus ending the possibility of Shawnee neutrality.

In many ways, William Henry Harrison serves as the antagonist in this biography. Harrison was the governor of the Indiana Territory in the early 1800s. Tecumseh repeatedly asked Harrison to nullify the land treaties made between the Native Americans and the US government, which Harrison refused.