‘Once Upon a Time in Mumbai Again’ is the story of Shoaib, an underworld don who came to power by killing his mentor and has extended his kingdom with the help of his best friend, Javed, and his former lover, Mumtaz. While visiting the area where he grew up, he meets Aslam, who becomes his accomplice.
The film begins where its predecessor ended, with reigning don Shoaib Khan (Akshay Kumar) earning respect after assassinating his mentor, Sultan Mirza (Ajay Devgn). Twelve years later he is still a charismatic, suave womaniser, who has extended his empire to the Mideast. Khan's only friends are Javed (Sarfaraz Khan) (who oversees his illegal work), his former love Mumtaz (Sonali Bendre), and Aslam (Imran Khan), a teenager Khan met during a visit to the slums in which he grew up.
An older Khan returns to Bombay to kill Rawal (Mahesh Manjrekar), who opposed his ambition to take the reins in Bombay. Although the city was his first love, rising starlet Jasmine (Sonakshi Sinha) wins his heart. Khan advances Jasmine's career by rigging awards, and showers her with gifts; she becomes obsessed with him. He sends Aslam and another trustworthy aide, Jimmy, to kill Rawal. Jimmy fails, accidentally killing his girlfriend, Sonia, and flees. He is soon captured by the police, hot on Khan's trail after learning about his arrival in Bombay. Jimmy, loyal to Khan, does not crack during his interrogation and is freed due to lack of evidence. The police intend to draw Khan out from hiding; he has eluded them for twelve years, and this is their last chance to take him on Indian soil.
Khan, suspicious that Jimmy has become a police informer, decides to kill him but Aslam offers to do the deed to deflect police attention. He, Dedh Tang and several thugs masquerade as rival biker gangs and stage a brawl. Plainclothes police officers try to control the chaos when Aslam corners Jimmy. When a police officer stops Aslam, Khan appears out of nowhere, murders Jimmy and injures the policeman. A chase ensues; the police fail to catch the two, who escape in Khan's Mercedes.
Although Khan has bought Jasmine a house, she rejects his advances, saying that she has never seen him as being more than a friend. Angry and disappointed, Khan slaps her and tells her to leave. He angrily destroys the set of the film she is cast in, leaving with her a twenty-four hour deadline to accept his proposal. Jasmine returns home to see that Khan has filled her house with expensive presents. Her mother is taken aback when Jasmine explains that Khan is a gangster with whom she'd prefer not to associate. Her family questions the sense in rejecting a man as powerful and dangerous as Khan.
Later in the night, Jasmine meets Aslam at his uncle's restaurant. He tries to explain his love for her, only to be interrupted and told that she is engaged and the two should stop seeing one another. Dejected and disappointed, Aslam meets with Khan, who seems unusually pensive. The two lament their relationships, not knowing they are both in love with the same woman. Just before Aslam is about to reveal the name of his romantic interest, a phone rings - Khan, jubilant, announces that his proposal has been accepted and orders Aslam to pick up his new "bhabhi," or sister-in-law.
Aslam arrives at the address Khan has given him and, much to his shock sees Jasmine walking towards his car. Initially angry that he is still following her, the two realize that they have been caught up in a complicated affair - that Aslam, unbeknownst to Jasmine, works for Khan, and that Jasmine was the one he had been sent to pick up. Before either can speak, a car containing Rawal and his henchmen arrives at a distance. Rawal shoots Jasmine, having learned of her relationship with Khan and hoping that hurting her lure the gangster into a vulnerable position.
Jasmine remains unconscious at the hospital as Khan arrives. He accuses Aslam of being in love with his fiancee - an accusation which Aslam denies as Khan reveals that he has masterminded a plan to murder Rawal and ensure his own dominance over the Mumbai underworld. Khan intends to fabricate a story of him feuding with Aslam to tempt Rawal and his rivals into contacting Aslam. The "news" reaches Rawal, who seems delighted at the prospect of being able to turn Khan's right-hand man against him.
When Rawal calls Aslam at the hospital, Aslam, now fully aware of Khan's feelings towards Jasmine, seems unsure whether to abide by Khan's plan. He reluctantly provides Rawal with an address, ending the phone call by telling him to "murder the bastard." Khan, lying in wait outside the address with a sniper rifle, kills Rawal and his henchmen when they arrive. Khan, having consolidated power, savours his victory and walks into a police station as a taunt to law enforcement. However, Dedh Tang accidentally reveals Aslam's love for Jasmine in the midst of celebration. Khan, infuriated, diverts the car to the hospital to confront Aslam, who has continued to stay with Jasmine as she recovers from being shot by Rawal. Knowing that his friend is in danger, Dedh Tang honks the horn of the car repeatedly after Shoaib and his henchmen enter the building, alerting Aslam to the danger and giving him time to escape. Entering to see an empty bed where Jasmine had before been laying, Khan realizes that Dedh Tang had given him away.
Khan sends his aide Akbar to kill Aslam after he and Jasmine flee to Aslam's uncle's restaurant in Dongri. Aslam assures Jasmine that Khan, though violent, would never hurt him. Their conversation is interrupted by a car's horn honking - running outside, Aslam is ambushed by Akbar after discovering the body of Dedh Tang, who has been killed by Shoaib for aiding the couple in their escape. Aslam, though injured and initially losing the fight, kills Akbar with a shovel. He calls Khan to tell him that the murder of Dedh Tang has, in effect, erased his deep-seated loyalty to his former boss. Khan responds by telling Aslam that sending Akbar was a mistake, as he must be the one to kill the man he views as also having betrayed him by "stealing" Jasmine. In the last scene, a bullet-ridden, dejected Khan reads a letter he was unable to give Jasmine in the cargo hold of a ship.
The story is told in retro-rap and with stylish designer double dons. This film has its moments, but it's not as compelling as the prequel.