Govind begins by reciting events from Chidambaram in the 12th century Chola empire of South India. Kulothunga Chola II, (Napolean) the King of the empire is a Saivite, believing in the Hindu deity, Shiva. The King wants to get rid of all temples of the deity Vishnu, followed by the Vaishnavites and intends to take a large idol of Vishnu from a temple intent on disposing it in the Bay of Bengal. However, Rangaraja Nambi (Kamal Haasan), a Vaishnavite, tries to stop the King from disposing his deity. Uncovering Nambi's plans to stop the idol's disposal, the King tells him to renounce his belief or be destroyed along with his idol. Nambi refuses to bow to any other god, despite pleas from his wife, Kothai Radha, (Asin Thottumkal) and is subsequently tied to the huge idol and both are thrown in the Bay of Bengal.

The scene switches to the week preceding the 2004 Boxing Day Tsunami, beginning on 20 December 2004. Govindarajan Ramaswamy, commonly known as Govind, is a biotechnologist working at a lab in California, USA. He works in an organization which had invented a deadly virus which has the potential to be the greatest bio-weapon ever made by man, with the actual matter being kept well protected. However during an announcement with George Bush, Govind's lab monkey breaches the security protecting the bio-weapon and swallows it, killing it and producing a devastating effect. Following this discovery, Govind wants to destroy it, with the only possible remedy being the mixing of the weapon with sodium chloride. But his boss, Dr. Sethu (Rajesh Toleti) at the organization has a different idea and attempts to sell it to terrorist organizations. Upon the discovery of this, Govind makes off with the vial containing the virus and flees to his friend, Suresh's (Sanjay) home. Suresh betrays Govind and informs the boss that Govind is at his house.

Suddenly Christian Fletcher (Kamal Haasan), who is an ex-CIA officer, also appears in the scene wanting the vial for his own nefarious purposes. At Suresh's house, Govind manages to escape without harm but Suresh and his Japanese wife, Yuka (Ann), are murdered by Fletcher. The escaping Govind, finds himself in a car with with another friend, Sairam, in whose belongings, the vial gets mixed up accidentally, sending the vial by mistake to Chidambaram in India. Unable to stop the flight, Govind finally manages to escape from the USA by sneaking aboard a cargo flight. Receiving intelligence on this issue, Fletcher decides to fly to India to recover the vial. Prior to leaving, he finds himself a translator in the Las Vegas pole dancer, Jasmine (Mallika Sherawat); also getting married to her before leaving. In Japan, Shingen Narahashi (Kamal Haasan), a Japanese martial arts expert and brother of Yuka, thinks it was Govind who killed his sister and comes to India, seeking revenge.

Upon arrival at Chennai airport, the vial is transfered to another plane and Telugu intelligence officer, Balram Naidu (Kamal Haasan) intervenes and questions Govind, who insists on talking to higher authorities but to no avail. As Naidu walks out of the room briefly, Fletcher invades the building taking Govind and a police officer, Bharath (Akash) hostage. The trio along with Jasmine are stopped at immigration but mange to escape after a Punjabi pop singer, Avtaar Singh (Kamal Haasan), faints and causes a frenzy at the airport. Eventually Akash gets shot and during this, Govind manages to escape from Fletcher and flees to Chidambaram in hope of finding the vial. Subsequently, Fletcher and Jasmine hire a driver, Broadway Kumar (M. S. Baskar) to transport them to Chidambaram as well.

The vial ultimately ends up at the house of a Brahmin family in Chidambaram. The vial, delivered in a parcel by the postman Prabhu (Vayapuri), is taken in by a 95-year-old, mentally retarded woman, Krishnaveni (Kamal Haasan), who lives in belief of receiving a parcel from her son, who perished in 1953. Govind pleads for it to no avail, but eventually changes the mind of Krishnaveni, after explaining the scientific threat to her granddaughter, Andaal (Asin Thottumkal). Krishnaveni responds by putting the vial inside the idol of the deity, Perumal, citing that God would destroy the weapon. Fletcher and Jasmine, eventually arrive in Chidambaram and Jasmine attempts to seduce Prabhu and Naidu's assistant, Ekambaram (Chitti Babu) to reveal Govind's location.

Govind tries to secure the vial before Fletcher and Jasmine reach them. Soon, Fletcher fires his gun near an elephant and it starts rampaging, with Jasmine getting badly hurt in the commotion. Lest she should say something, Fletcher shoots her dead. Govind tries to escape with the idol but Andaal, who worships the idol, tries to stop him. Eventually they both escape and after a long chase, they manage to reach the old Chola Temple, where the King watched the idol of Vishnu being thrown into the ocean in 12th century. Govind remembers that the vial should be kept cool so they bury the idol in cold sand and go in search of ice to maintain the temperature. As they stop to get ice, the pair find out they are being hunted by the police and that they are being portrayed negatively in the press. When they return they find that the quarry sand, where they planted the statue, is being stolen by illegal sand miners. The miners capture the duo as they try to reclaim the idol. Furthermore, their leader (Santhana Bharathi) attempts to rape Andaal when she shouts into darkness for help. Lights flash and Vincent Poovaraagan (Kamal Haasan), a Dalit who was been neglected by the society due to their caste arrive, along with a bunch of TV reporters, comes to question the theft of sand from quarries. Using this opportunity, Govind and Andaal escape with the idol.

They manage to escape using the sand lorries and on the main road, they collide with a car which contains a Muslim family within it. Govind helps the family out of the house, with the injured also including seven foot giant Kalifullah Mukhtaar (Kamal Haasan), furthermore they simultaneously escape from threats from Fletcher and Balram Naidu. Kalifullah's mother, Megha (K. R. Vijaya) begins to bleed and Govind with Andaal take her to the local hospital. At the hospital Avtaar Singh rests with a tumour in his throat posing potential danger to his vocal cords and thereby, his singing career. He checks into a hospital and the doctor gives him some medicines in a cooler. Govind also gets a cooler, similar to the one of Avtaar Singh, to preserve the idol and hence, the vial. In a lift, the coolers of Govind and Avtaar Singh are mixed up, and Avtaar Singh sets off for his concert. Govind meets Bharath again, with the police officer instructing him to meet Balram Naidu. Govind picks up the cooler which actually contains the medicine and sets off to the police station, thinking that it has the idol inside. Meanwhile, at the hospital, Fletcher arrests Andaal at gun point and takes her to Kalifullah's home. He makes a phone call to Govind to get back along with the idol. Govind retreats from the steps of the police station, only to be spotted by Balram Naidu and Shingen Narahashi. The entire police force follow Govind to Kalifullah's home hoping to arrest Govind and Fletcher. When Govind and Fletcher meet, they are surprised to see that the cooler box does not have the idol in it and Govind guesses that it should be with Avtaar Singh. With assistance from Kalifullah's father, Sheik (Nagesh), they escape to the concert hall. Balram Naidu brings the police and enquirers Kalifullah and the residents of the entire village regarding the escape of Govind. Subsequently he orders everybody to be stationed in a Mosque to hasten the inquiry.

Avtaar Singh finishes his predicted last musical performance, vomiting a lot of blood while singing. At the end of the concert, Govind and Fletcher are waiting for him to exchange the cooler box. Fletcher shoots Avtaar Singh in the throat and after little confusion, Govind and Andaal set off on a bike along with the idol and Fletcher continues to chase them. Govind and Andaal reach a construction site along with the idol. The sun dawns on December 26, 2004. Fletcher holds Andaal at gun point and Govind hands over the idol to Fletcher, only to confess later to Andaal that he had removed the vial from the idol. Balram Naidu reaches the spot in a helicopter and chases Fletcher. Govind and Andaal set off with the vial, with Govind realizing the urging need to preserve it.

Meanwhile, J. Raghavendra (P. Vasu), head of the illegal sand miners tries to cajole Vincent Poovaragan to give up his activities and join his side. Most of Poovaragan's members have deserted him, however Poovaragan remains unchanged. At the same time, President Bush and few others come to know that NaCl could destroy the weapon. Back in Tamil Nadu, Govind notices a couple of drainage cleaners who coat their bare bodies with crystal salt before getting into the drainage holes. He gets an idea and runs toward the sea, only to be stopped again by Fletcher and Govind is no match for Fletcher and Fletcher succeeds in securing the vial. While Govind is hurt badly, Shingen Narahashi comes to his rescue and fights against Fletcher, after he understands Fletecher had killed Yuka. Govind watches Shingen Narahashi break Fletcher's arms and legs. Fletcher helplessly and in frustration, curses India and breaks open the vial and eats it despite pleas from Govind who shouts not to do it and at the same time asks Shingen Narahashi to back away. Balram Naidu, in his helicopter has followed Fletcher all the way through till the beach. As soon the vial is open, he zooms in with his binoculars and the virus starts replicating rapidly in the atmosphere.

Almost immediately, the Tsunami strikes. Balram Naidu flees away in his helicopter. Govind, Shingen Narahashi and Andaal take refuge in a small boat while the decaying Fletcher gets washed away. The Mosque which hosts the inhabitants of Kalifullah's village is unstruck and the entire village is saved and they return the good will by helping the police in Tsunami relief. J. Raghavendra's house is struck and Poovaragan saves the children of Raghavendra, but gets himself killed in the fracas. During relief efforts, Krishnaveni believes Poovaragan to be her son and cries out of grief finally, breaking the barriers of her caste. Andaal expresses her love for Govind and at the same time, praises God who, according to her, has saved millions of lives through a Tsunami in place of the vial. Govind questions her theory by asking if a God would kill thousands of lives. As Govind and Andaal set off from the beach, an idol of Vishnu is shown to have brought back to the land by the sea through the Tsunami. It is also indicated that the bullet that struck Avtaar Singh's throat cleared off the cancer and he should be able to get back to singing in a span of six months.

The scene changes back to the Jawaharlal Nehru Stadium in Chennai where President Bush is invited to deliver his speech. After speaking, the Chief Minister of Tamil Nadu, M. Karunanidhi is invited to speak and credits roll by concluding in the Ulaga Nayagan song, showing the hardships of portraying ten different roles by Kamal Haasan.

* Jayaprada as Ranjitha Singh. After several films with Haasan throughout the 1980s, Dasavathaaram saw Jayaprada reunited on-screen with him. She beat several others to the role and portrayed the caring wife of Punjabi pop star, Avtaar Singh.

* Napolean as Kulothunga Chola II. Napolean portrayed the King who lived in 13th century Chidambaram during the Chola Dynasty, believing the rites of the Hindu god, Shiva. The scenes with Napolean were among the first shot, additionally, Napolean's off-screen persona as a politician helped the unit secure more relaxed rules for their shooting locations.