Seale grew up in Dallas and in California. Following service in the U.S. Air Force, he entered Merritt College, in Oakland, Calif. There his radicalism took root in 1962, when he first heard Malcolm X speak. Seale helped found the Black Panthers in 1966. Noted for their violent views, they also ran medical clinics and served free breakfasts to school children, among other programs.

In 1969 Seale was indicted in Chicago for conspiracy to incite riots during the Democratic national convention the previous year. The court refused to allow him to have his choice of lawyer. When Seale repeatedly rose to insist that he was being denied his constitutional right to counsel, the judge ordered him bound and gagged. He was convicted of 16 counts of contempt and sentenced to four years in prison. In 1970–71 he and a codefendant were tried for the 1969 murder of a Black Panther suspected of being a police informer. The six-month-long trial ended with a hung jury.

Following his release from prison, Seale renounced violence as a means to an end and announced his intention to work within the political process. He ran for mayor of Oakland in 1973, finishing second. As the Black Panther Party faded from public view, Seale took on a quieter role, working to improve social services in black neighbourhoods and to improve the environment. Seale's writings include such diverse works as Seize the Time (1970), a history of the Black Panther movement and Barbeque'n with Bobby (1988), a cookbook.