Ghajini centers on Sanjay Ramaswami (Surya Sivakumar), a rich businessman who owns a cell phone company named Air Voice and the events surrounding his relationship with Kalpana (Asin Thottumkal).Kalpana, an advertisement model, meets with representatives from Sanjay's company who come to request a business agreement and ends up telling her advertisement crew that she is Sanjay's love interest - after the crew mistakenly thought that the executives were sent by Sanjay to ask for her love. She has never met him, but soon exploits popularity from her "relationship" with him and even does an interview in a magazine.
Sanjay happens to hear about it on the media and wants to settle scores with her. On his way, he catches a fleeting glimpse of Kalpana (whom he doesn't know yet) helping handicapped children to cross a street, and experiences love at first sight. He moves on to confront Kalpana at her advertisement studio and is pleasantly surprised to realize that she is the same helpful woman he saw a while ago. He then chooses to hide his true identity, calling himself Manohar. Kalpana eventually falls in love with him without realizing he's Sanjay. Once, while on a train to Mumbai, Kalpana saves a group of young girls from abuse by a group of goons led by Lakshman (Pradeep Rawat).
After a few days, the same goons come to Kalpana's house in order to avenge their embarrassment. Incidentally, Sanjay arrives at the scene and fights off the goons, but during the ensuing fight, Kalpana is murdered. The irony showcased is that Kalpana never finds out that he is Sanjay. Lakshman then strikes the downcast Sanjay on his head severely with a metal rod. Sanjay survives the blow, but suffers from a short-term amnesia. At any given time, he does not remember anything that happened more than 15 minutes back, although he frequently has flashbacks of Kalpana's murder. He determines to take revenge on those responsible for Kalpana's death. The rest of the story is about how Sanjay, along with a medical college student Chitra (Nayantara), goes about finding Lakshman and the goons.