In 1975, Annie Mae Pictou Aquash, a 30-year-old Mi'kmaq from Nova Scotia, was shot and killed in South Dakota. The crime has remained unsolved for nearly thirty years. Aquash was a key member of the American Indian Movement (AIM), a group that used activism in the 1970s to fight for Indigenous rights. "The Spirit of Annie Mae" tells her life story and the circumstances of her murder. It's a tribute from those closest to her: her daughters, who hid with her from the FBI; the women she inspired to connect with Native culture; and fellow activists like Buffy Sainte-Marie and Minnie Two Shoes, who supported her. They continue to seek answers about why she was so violently killed. The film follows them as they honor a woman who inspired a generation of Indigenous people.