Elwood Blues, Dan Aykroyd, is released from prison after eighteen years and learns that his brother, Joliet Jake Blues Dan Aykroyd, has died. He’s picked up by Matara, a friend who works for his former drummer, Willie Hall, and who wants to help him get back on his feet. Before meeting Willie, Elwood asks to visit Mother Mary Stigmata at a hospital; she informs him that Curtis has also died but fathered an illegitimate son named Cabel Chamberlain, an Illinois State Police commander, and introduces him to an orphan named Buster J. Evan Bonifant to suggest mentoring him.
Against Stigmata’s advice, Elwood tracks Cabel down at his police headquarters to inform him of his real father and to recruit him to reform The Blues Brothers Band. Cabel, upset by the news and offended by the suggestion to join after seeing Elwood’s and Jake’s criminal histories, throws him out, where Buster steals his wallet; it contains enough money for Elwood to purchase a new Bluesmobile. Elwood and Buster begin tracking down members of the former band to recruit them from their current jobs. Willie runs a strip club and joins after it is burned down by the Russian mafia because Elwood enlisted the help of Willie’s barman, Mighty Mack McTeer John Goodman to try and convince them to leave the club alone, by getting two of the mobsters drunk and leaving them bound and gagged in an alley. Mack also joins the band as well, along with former member Matt “Guitar” Murphy Matt Murphy, who returns at the advice of his wife, Mrs. Murphy Aretha Franklin, who now runs a Mercedes-Benz dealership, as well as saxophonist “Blue Lou” Marini Lou Marini. Three members work at a radio station and quickly agree to join, and finally Murphy Dunne joins after his boss at a call center gives him permission.
The newly reformed band uses their old agent to book them a show. On the way to it, they are followed by Cabel and the Illinois state police, who are now looking for Elwood for stealing Cabel’s wallet earlier and believing that he has kidnapped Buster. While avoiding the police, Elwood interrupts a militia group meeting, unintentionally destroying their boat full of explosives they planned to use. The band arrives at the show to find they have been mistakenly booked as a Bluegrass band, but perform anyway. Afterwards, they evade capture by the police, but they catch up with them at a tent revival where Reverend Cleophus James James Brown is preaching. Before Cabel can arrest them, he has an epiphany brought on by Reverend Cleophus that he should join the band instead of being a police officer. The band evades capture once more, now with Cabel joining them, who the police believe is brainwashed.
The band continues on to their next booking, an audition for a Battle of the Bands put on by Queen Mousette Erykah Badu who Mack informs is allegedly a 130-year-old voodoo witch. Queen Mousette requests the band play something Caribbean; when Elwood explains they don’t play Caribbean music, she casts a spell on them to play anyway. She accepts the band into the battle; however, Elwood, Mack, and Cabel are turned into statues. At the show, Queen Mousette undoes the spell to allow the Blues Brothers to play against the Louisiana Gator Boys, a supergroup of blues musicians who win the battle. After the battle, the show is interrupted by the arrival of the Russian mafia and militia group from earlier; they are turned into rats by Queen Mousette. The Illinois state police arrive, but stand down after Cabel informs them that he is okay. Elwood suggests that the two bands jam together on stage. When Mother Mary Stigmata arrives, Elwood uses the performance as cover to say goodbye to Cabel and Mack and escape with Buster, with the police giving chase.
