On board a departing Air India flight, Farhan Qureshi (R. Madhavan) suddenly receives a call from Chatur Ramalingam (Omi Vaidya) claiming that he has found Rancho. He then causes an emergency landing by feigning a heart attack. Farhan fetches Raju Rastogi (Sharman Joshi) and they meet Chatur at a water tank in their old college campus; Chatur revealing that Rancho is in Shimla.

As they drive their way to Shimla, a flashback shows Farhan and Raju beginning their college year in the prestigious Imperial College of Engineering (ICE) in Delhi. They are joined by Ranchoddas Chanchad (Aamir Khan), known as "Rancho" . While Farhan takes engineering over photography to please his father, Raju takes the course to lift his family from poverty. Rancho, on the other hand, believes in hands on learning and tends to give unorthodox answers in class, coming into conflict with professors, in particular with the institution's director, Dr. Viru Sahastrabuddhe (Boman Irani), whom the ICE community nicknames as "Virus", and whose traditional and strict philosophies on education contrast sharply with Rancho's carefree love of learning. Meanwhile, Chatur, nicknamed “Silencer", is an arrogant Ugandan-born Tamil student with little knowledge of Hindi, who is obsessed with topping the exams.

Days later, the trio find a student named Joy Lobo (Ali Fazal) hanging in his room; his death caused by depression after Virus tells Joy's father that he will be unable to graduate. Rancho uses this to criticize Virus's method of teaching and show him how much pressure engineers face when they study - angering him further. After Rancho visits his friends' families, the trio then gatecrash a wedding to eat and meet and befriend Virus's daughter, Pia (Kareena Kapoor), who is a residency student at the city's hospital. When Virus's spots the trio, he summons Farhan and Raju on the next school day and threatens their families income. During a Teachers Day celebration, Chatur is humiliated when he delivers a Hindi speech modified by Rancho, and bets Rancho that ten years later,they would see who is more successful. Sometime later, Rancho saves Raju's dying father with the help of Pia.

One night during their senior year, the three friends drunkenly break into the Sahastrabuddhe residence to propose to Pia. As the three friends escape, Virus recognizes Raju, and threatens to expel him unless he writes a letter implicating Rancho in the break-in. Unwilling to betray Rancho, Raju attempts suicide and ends up in a coma. With intensive care and support from his friends and Pia, Raju recovers in time for a corporate job interview. Meanwhile, Rancho and Pia post Farhan's letter to his favorite photographer, Andre Istvan, who offers him a position as assistant. After advice from Rancho, he communicates his dream to his father, who gives his blessing.

Infuriated by Rancho's influence, Virus sets a difficult final exam to fail Raju. Pia tries to help the trio by revealing to them the location of the exam paper, but Virus finds out and expels them. Pia confronts Virus about her brother who committed suicide because he couldn't meet Virus' expectation of clearing the engineering exam. That same night, Virus' pregnant elder daughter Mona goes into labor during a heavy storm which cuts off all traffic and electricity. Rancho and the other students use their engineering knowledge to deliver the baby with the help of Pia over video call. A grateful Virus finally acknowledges Rancho as an extraordinary student, allowing the three to graduate. On graduation day, Rancho disappears shortly after the ceremony ends.

Returning to the present, Farhan is a successful wildlife photographer, Raju is married and settled with his family in a comfortable lifestyle with a corporate job, and Chatur is the vice president of a reputed corporation in the United States. None of them have heard from Rancho since graduation. Arriving at Shimla, they meet a man who turns out to be the real Ranchoddas Chanchad. From him, they learn that the Rancho they knew was actually "Chhote", an orphaned servant to the Chanchad family. Ranchoddas' father arranged for Chhote to attend ICE in his son's name, so that his son could take credit for the degree. Ranchoddas provides Chhote's address in Ladakh, where he is a school teacher. On the way, they pass Manali and rescue Pia from marrying her materialistic boyfriend Suhas over Chatur's objections; Chatur hurries to seek a business deal with world-renowned scientist and businessman with 400 patents, Phunsukh Wangdu.

Upon arrival in Ladakh, the four find the village school, witnessing young students' inventions that resemble Rancho's own college projects. Raju, Farhan, and Pia then happily reunite with Rancho but Chatur insults Rancho, and asks him to sign a statement that he is the less successful one. Without comment, Rancho does so. As Chatur walks away in triumph, Rancho reveals himself to be Phunsukh Wangdu much to his friends' and Pia's surprise. A horrified Chatur accepts his defeat and begs him to sign the contract while Pia and the three friends run away laughing.

• Aamir Khan as Ranchoddas "Rancho" Shamaldas Chanchad / Chhote / Phunsukh Wangdu, one of the titular trio in the engineering college who vanishes after graduation and whom his two friends hunt him for 10 years, while telling stories of their time in college together. Rancho, as a student, was conspicuously ingenious and angry at the inhumanity of the school system. At the end of the film, he is shown to be a famous scientist, entrepreneur and business magnate who also teaches young children when he takes a break from researching.
• R. Madhavan as Farhan Qureshi, the film's narrator and one of the trio whose father persuades him to study engineering over his dream career of wildlife photography; in the end he is shown to have published several books of photographs.
• Sharman Joshi as Raju Rastogi, another of the trio who comes from an impoverished family with a mother who is a retired school teacher and a paralyzed father who worked as a postman. In the flashback story, his family was unable to afford the car that would be demanded as a dowry for his sister. In the present story, he is a settled married man in Delhi who has freed his family from poverty by becoming a wealthy executive.
• Kareena Kapoor as Pia Sahastrabuddhe, Virus' younger daughter, an intelligent and capable doctor. Despite her father's disapproval, she and Rancho fall in love.
• Boman Irani as Dr. Viru Sahastrabuddhe, the college's strict director known as "Virus" and Pia and Mona's father who acts as the film's antagonist. He stubbornly sticks to a doctrinal method of teaching, putting him at odds with Rancho. At the end, he is shown to have changed his doctrinal methods of teaching.
• Omi Vaidya as Chatur Ramalingam, a Ugandan-Indian educated in Tamil-speaking Pondicherry who has little knowledge of Hindi. His habit of being gassy due to consumption of pills to enhance his memorization earns him the nickname Silencer. In the present story, he is vice-president of an American company who only discovers his success being overshadowed by Rancho in the end of the film. Baradwaj Rangan of the New Indian Express wrote that Chatur being a Tamil from Uganda makes him "twice removed from the North Indians around him — a stranger to the nation as well as the national language."
• Rahul Kumar as young Manmohan (nicknamed Millimetre), and Dushyant Wagh as adult Manmohan (Centimetre). As an adolescent, he earns a small living by doing errands for students, such as laundry, finishing assignments, and getting groceries. Rancho persuades him to buy a school uniform and sneak into school to gain an education. Later he becomes an assistant to Rancho/Phunsukh Wangdu in Ladakh.
• Mona Singh as Mona Sahastrabuddhe, Pia's elder sister and Virus's first daughter.
• Parikshit Sahni as Mr Qureshi, Farhan's father, a strict but loving parent who just wants his son to be happy.
• Farida Dadi as Mrs Qureshi, Farhan's mother, a loving and caring parent.
• Amardeep Jha as Mrs Rastogi, Raju's mother, a retired schoolteacher and dedicated mother.
• Javed Jaffrey as the real Ranchoddas Shamaldas Chanchad. It is from him that Raju and Farhan learns the truth: the Chanchad's father sponsored an orphaned servant boy called 'Chhote', who had demonstrated his intelligence and love of learning, to earn a degree in his name, while the real Ranchoddas was in London. He does appreciate what Chhote did for him, and tells Raju and Farhan where to find him.
• Arun Bali as Shamaldas Chanchad, father of Ranchoddas Shamaldas Chanchad.
• Ali Fazal as Joy Lobo, a student with a passion for machines. After Virus tells him that he will not graduate, he commits suicide.
• Akhil Mishra as Librarian Dubey
• Rohitash Gaud as Ranchoddas'( Real Ranchodas) servant
• Achyut Potdar as Machine Class Professor
• Madhav Vaze as Joy Lobo's father.
• Olivier Sanjay Lafont as Suhas Tandon, Pia's ex-fiancé, who cares only about money and ostentation.
• Jayant Kripalani as a company head who conducts Raju's job interview.
• Atul Tiwari as Minister in Auditorium
• Rajeev Ravindranathan as ragging senior student

Principal photography began on 28 July 2008. Hirani and his team left in late August for the shoot with the principal cast. The film was shot in Delhi, Bangalore, Mumbai, Ladakh, Chail and Shimla. Aamir and rest of the cast began shooting in early September. Hirani planned to wrap up the film by December. The first scene was shot in an aircraft with Madhavan. From Mumbai, the crew and cast comprising Aamir and Kareena went to Ladakh for a 20-day schedule. Filming of the ICE college scenes took place at the Indian Institute of Management  Bangalore campus for 33 days as a part of the second schedule of production. The dormitory scenes were filmed at the institution's female dormitory block.

The film is distinctive for featuring real inventions by little-known people in