Donnie Brasco tells the story of FBI undercover agent Joe Pistone, aka Donnie Brasco (Johnny Depp), who in the 1970's infilrated the mob in what was to become one of the most successfull mole operations ever. In the name of justice, Brasco leaves his family behind and takes on the persona of a gangster - the "jewel man" Donnie Brasco - who must prove his absolute loyalty and willingness to commit crimes to be accepted into a mob family. To gain greater access to the inner Bonanno operations, Brasco maneuvers his way into the confidence of Lefty Ruggiero (Al Pacino), a cynical, aging hit-man who never made it into the big-time and sees a new future for himself with this smart, young thief. Risking his own reputation, Lefty vouches for Brasco and enlists him as his protege. This is exactly what Brasco wants but it doesn't go as planned. Lefty's fidelity and friendship makes it hard for Brasco to distance himself emotionally. The man who should be his enemy, instead, becomes his trusted partner.

Meanwhile, Brasco tries desperately to keep a balance with his real-life family - to somehow return home and try to be the caring husband to a wife he cannot tell the truth to and a loving father to kids he never sees.