Scientist Rohit Mehra lives with his son Krishna Mehra (both played by Hrithik Roshan) in Mumbai. Krishna is married to Priya (Priyanka Chopra), a journalist for Aaj Tak. Rohit works in a research institute for the Indian government and Krishna, while moonlighting as the superhero Krrish, is regularly fired from various day jobs due to lack of attendance. Rohit is researching on a device that will bring life to dead tissues by the use of solar energy. Despite several attempts, he fails to complete the experiment due to the high intensity of sun rays. On a usual day, Krishna loses his job from the security wing of a company when he hears news about an aeroplane whose front tyres are stuck due to some malfunctioning which creates high risk, even if landed, it may explode and so will the passengers inside. Krishna immediately changes himself to Krrish and saves the plane from accident by holding the landing gear in place to allow the tyres to support the nose of the craft.
A few days later, Rohit hears about a deadly disease spreading in Namibia due to a virus whose antidote has not yet been discovered. He consults his friend Dr. Varun Shetty (Arif Zakaria) about the situation. Meanwhile, Shetty receives a phone call from Dr. Alok Sen (Asif Basra), a scientist working for Kaal Laboratories who insists on meeting him in order to reveal information about the virus and its antidote. Both Sen and Shetty are, however, murdered by Kaya (Kangana Ranaut), a shapeshifting female mutant. She is the henchwoman of Kaal (Vivek Oberoi), a handicapped evil genius who possesses telekinetic powers. Kaal creates a team of human-animal hybrids called "maanvars", with distinct physical powers in order to cure himself but fails. Later it is revealed the virus in Namibia was spread by Kaal himself to incur huge profits by selling its antidote, the singular source of which is his blood.
Rohit discovers that the virus, which is fast spreading through Mumbai, has no effect on Krishna, the pregnant Priya or himself. He, thus, makes an antidote by using the blood from Krishna's bloodstream which he spreads with the help of explosions. An enraged Kaal sends his mutants to attack Rohit and find out how an antidote was developed without using his own blood. Krrish manages to save Rohit, but Priya is injured and hospitalised. Krrish, however, manages to defeat the mutant Striker (Gowhar Khan). Kaya, carrying out Kaal's instructions, shapeshifts into Priya while Priya is kidnapped by Kaal. Posing as Priya, Kaya leads Krishna to believe that Priya has lost her child, and continues to live with the Mehras. While finding the truth behind the antidote's formula she develops an attraction towards Krishna. Failing to get answers about Frog Man's involvement with the virus attack, Rohit travels to Singapore to seek answers from Dr. Siddhant Arya's (Naseeruddin Shah) partner, where he is kidnapped by Kaal's men. Meanwhile, Krishna discovers the true identity of Priya; furious, he reveals himself as Krrish to Kaya and orders her to take him to Kaal's laboratory. Having fallen in love with Krishna, Kaya decides to help rescue his wife.
At Kaal's laboratory, it is revealed that Kaal is Rohit's son, who was created by an experiment conducted by Dr. Arya while Rohit was held hostage by him years earlier. The child was born handicapped, and was thus given away to an orphanage from where he was adopted by a wealthy man (Mohnish Behl). Kaal uses Rohit's bone marrow to successfully cure his handicap. Meanwhile, Kaya saves Priya and unites her with Krrish; she is, however, murdered by Kaal for her disloyalty. Kaal subsequently murders Krrish, and dons a metal suit. Deeply disturbed by his son's death, Rohit decides to re-use his failed experiment to bring dead tissues to life in order to save Krishna. This time, however, he absorbs the excess energy himself. The process simultaneously kills Rohit and transfers his powers to a revived Krishna. Meanwhile, Kaal threatens to dest