[7][8] Keshishian moved to Los Angeles following his graduation, where he directed music videos for artists including Bobby Brown, Run-DMC and Elton John.

[9] Initially commissioned by HBO to shoot backstage footage of Madonna at the start of the Blond Ambition tour in Japan, Keshishian filmed "everything, off and on stage."

[9] The strength of the Japanese footage, as well as the rapport between Keshishian and Madonna, led to making Truth or Dare, which became the biggest grossing documentary of its time.

In an article that marked the 30th anniversary of the film's release, the Guardian reported that Keshishian was "less fascinated by Madonna’s admittedly impressive onstage show than by the freewheeling circus of her backstage life, surrounded by her self-described “family” of assistants, adjuncts and predominantly queer backup dancers...Keshishian likened the crew to the bawdy ensemble of a Federico Fellini film; Truth or Dare, in turn, fashioned itself as the La Dolce Vita of rockumentaries, chaotically freeform and in thrall to sensuality and decadence, and shot largely in limber, grainy black-and-white for maximum vérité cred.

[citation needed] In 2011, with Madonna, he co-wrote the screenplay for the film W.E..[14] In 2015 Keshishian directed the music video for Selena Gomez' song "Hands to Myself".

[15] In a review in the New York Times, Chris Azzopardi wrote that the film was "sincere and soul-baring" and that Keshishian "worked the same kind of magic on Madonna for Truth or Dare," noting that My Mind & Me "looks outward, framing struggle as the human condition.