Upon his release from prison, Elwood Blues (Dan Aykroyd) learns that his brother Jake is dead and that their partner and surrogate father Curtis, also gone, had an illegitimate son named Cabel. He searches out this "half-brother," who turns out to be an Illinois state police commander (Joe Morton), and tries to convince him that his true calling is music. Meanwhile, the nun who raised Elwood as a child wants him to be a mentor to Buster (J. Evan Bonifant), a 10-year-old orphan. "God works in mysterious ways," she tells them. Elwood adopts this mantra as his own as he sets out to reassemble his band. With his propensity for getting in trouble, this Blues brother needs all the help he can get.

Elwood finds the band members established in other careers, but after they produce music again — in some hilarious and musically inventive production numbers — they decide to go on the road together. Mighty Mack (John Goodman), a former bartender, proves to be a fine singing talent. Buster turns out to be an adept on the harmonica and a great dancer. Even Cabel joins them. On the way to a battle of the bands hosted by a voodoo queen, these stalwart souls have several run-ins with the police, the Russian mafia, and a white supremacist militia group.

John Landis directs this ragtag sequel to the popular 1980 comedy with high regard for its musical talent, peppering the story with cameos by such legends as B. B. King, Aretha Franklin, James Brown, Junior Wells, Wilson Pickett, Eric Clapton, and Taj Mahal. (After the grand finale, don't miss the exhilarating music accompanying the closing credits.) "There is nothing better than music as a means for the upliftment of the soul," Sufi master Hazrat Inayat Khan observed. God does work in mysterious ways.