Mumbai Meri Jaan tells the story of five different people whose lives are affected by the 2006 Mumbai train bombings. Rupali Joshi (Soha Ali Khan) is a successful reporter who is getting married in two months. Nikhil Agarwal (R. Madhavan) is an environmentally conscious executive who rides the train to work every day and is expecting his first child. Suresh (Kay Kay Menon) is a struggling computer tech who spends his time loafing at a local cafe and criticizing Muslims. Meanwhile, Sunil Kadam (Vijay Maurya), struggles with the corruption and inefficiency of the Mumbai police force and his boss, Tukaram Patil (Paresh Rawal), who is nearing retirement.
On 11 July Nikhil and Suresh are in the second class compartment of a train when a bomb goes off in the first class compartment. The two survive, but Nikhil is too afraid to take the train again and is diagnosed with acute stress disorder. Suresh becomes obsessed with punishing the city's Muslims and is only stopped from antagonising them by Kadam and Patil on patrol. Kadam and Patil abuse a street vendor named Thomas (Irfan Khan) who begins calling in fake bomb scares at malls to relieve his feelings. After an elderly man suffers a heart attack while the police are evacuating one mall, Thomas feels guilty and decides to stop. Rupali, who rushed to the scene of the bombings to cover the story, is devastated when she discovers that her fianc? died in the blasts. Her grief is augmented when her news channel she works for tries to exploit her story for ratings. Meanwhile, Suresh pursues a Muslim that he suspects of being a terrorist. However, after Patil stops him and lectures him on communal harmony, he befriends the Muslim man.
After Nikhil's wife goes into labour he is forced to take the train to get to the hospital. Mumbai stops for two minutes while the city observes a moment of silence in tribute to those killed in the bombings as Patil finally retires from the police force and Kadam forgives him for his corrupt actions. Nikhil overcomes his fear of trains and Thomas gives a rose to the elderly man whose heart attack he caused.