Sunita (Jiah Khan), a medical student, is investigating the amnesia case of Sanjay Singhania (Aamir Khan), the chairman of Air Voice, a telecommunications company. She does so against her professor Dr. Debkumar Mitra's (Anjum Rajabali) wishes, in spite of Sanjay being under criminal investigation. Sanjay, who loses his memory every 15 minutes, uses a system of photographs, notes, and tattoos on his body to recover his memory and remember his mission of avenging the murder of his fiance Kalpana Shetty (Asin), who was killed by a criminal kingpin, Ghajini Dharmatma (Pradeep Rawat). Sanjay does not remember Ghajini's face. He only has a name, which was uttered by Kalpana in her dying moments.At his home, Sanjay has a wall full of clues, notes, and photos of people he has pursued and killed in search of Ghajini. This is the way that he reminds himself of his remaining life's mission. He also has tattoos all over his body with crucial clues collected over time.Sunita meets Sanjay at the hospital for his check-up and speaks to him about his system of remembering things. Sanjay takes Sunita's photo as well, to remember her.Police officer Arjun Yadav (Riyaz Khan), who is investigating a murder (of a goon from whom Sanjay gets Ghajini's phone number) that Sanjay committed (he is searching for Ghajini), knocks Sanjay unconscious in a scuffle at his apartment and finds two diaries in his drawer. Arjun had found a bus ticket at the murder scene. Further investigation reveals the bus and the day on which the ticket was issued. The conductor reveals that the ticket belongs to a guy who keeps forgetting to take his change or forgets to take a ticket.He learns that Sanjay, a successful entrepreneur (he heads a mobile company called Air Voice), met Kalpana, a struggling model, after he planned on installing an advertising billboard above her apartment. When his agents arrive at Kalpana's model shooting site to negotiate with her about it, Kalpana's boss, advertising veteran Satveer Kohli (Tinnu Anand), misinterprets this as a romantic advance and, in a view of Sanjay's fame and fortune, encourages Kalpana to accept the overture. Kalpana can see that this is a misunderstanding, but like the special treatment she is getting from Satveer and decides to play along.Kalpana also decides to pose as Sanjay's girlfriend. she even gives a couple of magazine interviews posing as Sanjay's girlfriend. As soon as Sanjay finds out about the false rumor, he plans to meet Kalpana to confront her but fails (as Kalpana doesn't allow him to speak and gives him fantastic stories about, she met Sanjay), as he starts to like her after seeing her altruistic nature.He poses as Sachin, a newcomer model, and lies to Kalpana about himself. Soon, he falls deeper in love with her. Sanjay understands why Kalpana played the charade of posing as Sanjay's girlfriend. At the end of the first diary, on 31st December, Sanjay, still playing Sachin, proposes to Kalpana who, taken aback by such a sudden gesture, asks for the night to think over it. He decides that if she would agree, then he would reveal his true identity to her, but, if not, then he would quietly walk away from her life as Sachin.As Arjun starts reading the second diary, Sanjay attacks him and ties him up. Sanjay steps out of the apartment as he knew of Ghajini's appearance at a college cultural function, the card to which he had found in the goon's house. At the function, Sanjay sees Ghajini for the first time and takes his photo. He tries to kill Ghajini but ends up killing one of his bodyguards. Sunita had seen Sanjay at the college function.Sunita locates Sanjay's apartment, finding Arjun and learning of Sanjay's murder plot to kill Ghajini (from his wall and the detailed notes and the photos of goons he killed). She steals his diaries and frees Arjun. As she and Arjun escape from Sanjay, Arjun is hit by a bus. Sunita manages to escape when Sanjay loses his memory again after 15 mins.Sunita then informs Ghajini about the fact that Sanjay is coming to him to kill him. Sanjay finds out about this (Sanjay was at Ghajini's house to kill him, when Sunita called with a request to get her photo back from Sanjay) and goes to attack her at her dormitory, where he is arrested and given a sedative. Ghajini is informed by the police (They find phone numbers tattooed to Sanjay's body and one of the numbers belonged to Ghajini) about Sanjay's belongings and he poses as Sanjay's friend at the police station. Soon Sanjay's employees and doctor arrive and take him home. Ghajini waits for everyone to leave and then his men destroy his pictures and cover his tattoos, thus leaving him with no memory about the past.After Sanjay gets arrested, Sunita reads the diaries. She finds out about Kalpana. In the second diary, Kalpana accepts the proposal, but on the condition that she marry only after she purchases three ambassador cars, due to a past (her dad had 3 ambassador cars and a travel agency but was defrauded by her uncle. That day she vowed to not marry till those 3 cars were restored). One thing leads to another, and Sanjay decides on taking her the truth about himself later. The diary ends abruptly when Sanjay has to go overseas for a few days to sign a mega deal for telephone services in London. Before leaving, Sanjay gifts a flat to Kalpana, by disguising it as a lottery win from Air Voice.After some research, Sunita eventually learns Kalpana traveled to Goa, where she stumbled across and freed a group of girls from a sex trafficking ring orchestrated by Ghajini. Sanjay returns home and finds Kalpana stabbed. Ghajini hits Sanjay in the head with an iron rod which results in brain injury, before killing Kalpana with the same rod, in front of him. All of this was revealed to Sunita by a lady constable who was involved in the case and had tried to warn Kalpana by informing of Ghajini's plans to kill her.Feeling guilty of doubting him, Sunita goes back to Sanjay and reminds him of Kalpana's murder and helps him track Ghajini to his local area. Sanjay then kills his men but has a memory loss fit while searching for Ghajini, who takes advantage of the situation and stabs Sanjay. As he prepares to kill Sunita the same way he killed Kalpana, Sanjay recovers his memory and kills Ghajini with the iron rod.Six months later, Sanjay is at an orphanage named after Kalpana, helping everyone like she did, and trying to heal. Sunita gifts him the cement pad with Sanjay and Kalpana's foot impressions, and he feels Kalpana beside him, as the screen pans out in a fading sunset.