The film opens with two cousins – Heena (Asin Thottumkal) and Bobby (Jacqueline Fernandez), the daughters of two opposing families who hate each other very much – start quarreling over something relating to their duties of Animals' Law Authority. Their fathers, Chintu (Rishi Kapoor) and Dabboo (Randhir Kapoor), are half-brothers who hate each other to the very core. Even their wives hate each other. Chintu wants the richest son-in law for his daughter, Heena, while Dabboo too wants the same for his daughter, Bobby. Aakhri Pasta (Chunky Pandey), a marriage counsellor, is ordered by both Chintu and Dabboo to find the best son-in-law. Aakhri Pasta brings Mr. kumar (Virendra Saxena) to discuss Babani's son Jai.

When Chintu misinterprets one of Aakhri's comments, who says that Jai looks neither like his mum or dad and may be an illegitimate child. Mr and Mrs. Babani did not hear Aakhri's comments and Chintu verbally abuses Babani while shouting. Babani suffers from a condition that affects his heart when he hears loud noises. Due to Chintu's shouting, Babani suffers a heart attack, landing him in a hospital. Babani's son Jai (Shreyas Talpade) comes to know of this and gets angry, then vows revenge, telling his friend Jolly (Ritesh Deshmukh), who is the son of billionaire J.D. (Mithun Chakraborty), to go to Chintu, agree to marry his daughter and then break off the wedding at the last minute. Jolly is busy trying to introduce his girlfriend J-Lo (Zarine Khan) to his own father and does not want to get involved. He suggests Max (John Abraham), their former college mate and a pick-pocket, to do the job. Jay goes with Max as his driver but somehow, they end in the wrong house and go to Dabboo's house.

Jai and Max later find out their mistake. Jai, still wanting revenge, doesn't know what to do and Jolly suggests another former sleazy college mate, Sunny (Akshay Kumar). Jolly goes with Sunny as his bodyguard because Max and Sunny are sworn enemies and as Dabboo's house and Chintu's house are right next to each other, their plan may get destroyed. Sunny and Jolly encounter a crocodile and Max and Jay encounter a snake each of the girls has as their pets. They manage to survive the attack.

While Heena and Bobby are at a cruise, they accidentally end up on an island. Max and Sunny become friends again, when Sunny tells him the truth about his colledge girlfriend who forced herself on Sunny and pretended that Sunny was touching her incorrectly. While Heena and Bobby become friends too as Bobby helps Heena remove a thorn that pricked her back, They find a resort and go home. Dabboo gets Jolly (Max/John Abraham) engaged to Bobby and Chintu gets Jolly (Sunny/Akshay Kumar) engaged to Heena. The day of the engagement, Chintu blindfolds Jolly, Sunny, and Heena and takes them to J.D.'s house. After seeing the real Jolly holding Sunny's garland, J.D. believes that Jolly got engaged to Heena. Luckily, Sunny convinces him. Jolly calls them at midnight and reveals his father's secret of being Jagga Dacoit. He also reveals that his real name is Jwala. After Sunny fools Chintu, Chintu calls Dabboo in excitement and tells him that his daughter, Heena, is getting married to Jolly, the son of J.D. Confused, and believing Max to be Jolly, Dabboo takes Max and Bobby to J.D.'s mansion. Sunny handles the situation well by fooling J.D. by taking the name of Goddess Bhadrakali as he is his true devotee and tells him that Max is Jolly's friend and Bobby is Max's fiancé (though actually it is true) and Max's father is against his and Bobby's marriage. J.D. then welcomes Bobby, Max and her family to his house and tells them to stay there till Bobby and Max's marriage.

Batuk Patel (Boman Irani) arrives with his daughter Parul (Shazahn Padamsee) to make things worse. Jai and Jolly/Jwala come to receive them from the airport. But when they see Parul, Jai and Jolly/Jwala lie that Jai is Jolly. Parul becomes happy hearing this as they secretly love each other.) J-Lo gives Jolly/Jwala the ultimatum  — take me to your house or forget me. To help Jolly/Jwala, Sunny lies to J.D., saying that J-Lo is his fiancé, and J.D. again agrees to let her live there as Sunny takes the name of Goddess Bhadrakali. Sunny and Max lie to their respective fathers-in-law that the other guy is the son of J.D. and a maid servant in the mansion. This creates a lot of confusion.

When Sunny's father as well as Max's 'Guru' tells them never to break anyone's heart, Sunny and Max tell the truth to Heena and Bobby. Enraged, Bobby and Heena slap Max and Sunny respectively and tell them that they never want to see their faces again. But thinking that instead of telling the truth, Sunny and Max could have done more wrong with them, the two sisters forgive the two boys on the very next day. There Jai and Jolly also let off their plan of revenge on Kapoors on Jai's father's advice. Then Heena proposes to Sunny in Sunny's style and Bobby proposes to Max in Max's style.

On the day of the four couples' marriage, J.D. and the other brides' fathers learn the truth about the grooms and that they have been lying all this time. Finally Bobby and Heena convince their fathers to forget their enmity and live together as blood brothers. Chintu and Dabboo join hands and so do their wives. But J.D. was not convinced by them telling the truth, so he turns back into Jagga Dacoit and starts frightening the families with his gun. He tries to shoot Sunny with his gun as Sunny runs towards J.D. to save him from the falling chandelier and then he understands what was happening. In the end, all the grooms get married to their respective girlfriends.

• Akshay Kumar as Sunny
• Riteish Deshmukh as Jolly
• John Abraham as Max
• Shreyas Talpade as Jai
• Virendra Saxena as Mr. Babani
• Asin Thottumkal as Heena
• Jacqueline Fernandez as Bobby
• Zareen Khan as J-Lo
• Shazahn Padamsee as Parul
• Rishi Kapoor as Chintu
• Randhir Kapoor as Dabboo
• Mithun Chakraborty as JD / Jagga Dacoit
• Boman Irani as Batook Patel
• Chunky Pandey as Aakhri Pasta
• Suparna Marwah as Sweety
• Neelu Kohli as Dolly
• Johnny Lever as Mithai Vishwas Rao Patil
• Vindu Dara Singh as Sosa
• Malaika Arora Khan as Anarkali (cameo and Item Number)
• Ushoshi Sengupta as Sonia (cameo)
• Ranjeet as Dr. Ranjeet V. Asna K. Pujari "The-rapist"

The sequel of Housefull was confirmed by producer Sajid Nadiadwala on 30 September 2010. The filming started on 9 June 2011 in London and Peterborough. The second schedule started from 1 October 2011 in Filmistan Studio, Mumbai and the last schedule was shot in December in Thailand, with one of the locations being the Sheraton Krabi Beach Resort. Sajid Nadiadwala hired a Hollywood action-set for Akshay Kumar's character.

The full album released on 22 February 2012. The making of the song "Papa Toh Band Bajaye" was leaked to YouTube in early January 2012. Singer Abhijeet Bhattacharya filed a lawsuit against the film's producers, saying that the melody for "Do U Know" had been copied from his 2005 song "Baje Jo Bansi". The lyrics were penned by Sameer, and the songs were composed by Sajid-Wajid.

The film score was composed by Sandeep Shirodkar.

Though the film was initially expected to release on 1 June 2012, it was announced on 30 September 2011 that the film would be releasing on 5 April 2012. The film had an earlier release in UK on 31 March 2012 due to the Easter holidays. Housefull 2 got a 2700-screen release, the fourth largest release i