The themes of The Yemassee by William Gilmore Simms include colonization, indigenous resistance, solidarity, father/son relationship, betrayal, and indigenous genocide. The novel follows the lives of Yemassee chiefs and individuals as they navigate living under colonial invasion from British settlers and militias. Colonization and indigenous genocide is discussed as the Yemassee people are continuously attacked and have their land encroached on by the British colonists. Sanutee eventually is killed along with the Yemassee resistance in general, which represents the indigenous genocide that occurred throughout the lands now known as "North America." The novel provides a deeply mournful depiction of a family and entire community thrown into upheaval by colonization and colonial violence.

Many within the Yemassee tribe begin fighting back against the white settler invasion of their lands, while some of the Yemassee chiefs betray their people by agreeing to sell their lands to the British. Solidarity and indigenous resistance is explored as folks band together to not only fight the settlers but fight against those within their own tribes who are willing to sell them out.

The father/son relationship theme is explored through Sanutee's and Occonestoga's relationship as Sanutee does not approve of Occonestoga's relationship with alcohol, which Sanutee understands to be an aspect of white settler society. The relationship continues to be strained as Occonestoga continues to form relationships with whites settlers. Occonestoga eventually chooses to betray his father and his tribe in general by agreeing to become a spy for the white settlers, and to report on the Yemassee's plans to fight back against the white settlers. Sanutee is completely dismayed by this betrayal and sentences Occonestoga to death. This relationship between father and son is essentially destroyed by colonization, indigenous genocide, and the broken relationships and betrayals that occur when people are thrust into a war zone.