Elwood Blues, the brother of the late Joliet Jake Blues, is released from prison and puts together a new band to save their childhood orphanage from being closed down. They set out on a mission to find talented musicians and battle against the Russian Mafia, the police, and a right-wing militia group.

Jake Blues rejoins with his brother Elwood after being released from prison to save their old R&B band and the Catholic home they grew up in, outrunning the police as they tear through Chicago. With the help of their old friend Curtis, Reverend Cleophus James, and their band members, they must put on a concert to raise the money needed. The duo faces various obstacles, including a mystery woman seeking revenge, angry Nazi protesters, and a car chase through the streets of Chicago. In the end, they successfully raise the money and are captured by the police.