Hera Pheri ended with the trio of Raju (Akshay Kumar), Shyam (Suniel Shetty), and Baburao Ganapatrao Apte (Paresh Rawal) rich and rolling in money. Phir Hera Pheri tells the story of what happens after they become rich.
The film opens with a prologue bringing the audience up to date, stating that each has suffered a personal loss as well as a gain. They all became rich, but Shyam lost his love, Anuradha in an automobile accident, Raju's mother has died after battling a disease and Baburao - despite having not much to lose in the first place - has lost the little commonsense that he had possessed.
The three men are living life king size in a massive bungalow and splurging on various luxuries. Raju hears about an idea for doubling his wealth from a con woman Anuradha (Bipasha Basu) who is claiming to be a bank manager, and he convinces Shyam and Baburao to go along with it. Raju first arranges for Rs. 30 lakhs from Shyam and Baburao and then a further 50 lakhs by selling their bungalow. He convinces a small-time goon, Pappu (Rajpal Yadav) to contribute the balance of Rs. 20 lakh so that he can come up with the minimum deposit of Rs. 1 crore, which Anuradha has promised to double.
The trio invest the money and three weeks later realise that it was all a scam and that they are now penniless. The goon is also in trouble because he had borrowed money from a lisping but dreaded gangster, Tiwari (Sharat Saxena), who will kill him if he doesn't pay up. Raju, Shyam and Baburao now have three days to come up with Rs. 40 lakhs to pay back the goon or else they will themselves be killed. They have to leave their bungalow and live in a chawl (tenement) where Anjali's (Rimi Sen) father is an accountant.
There they steal drugs from their neighbor (Johnny Lever) who has himself stolen the drugs from another don Nanji Bhai (Milind Gunaji). The drugs are worth about Rs. 3 crores (thirty million). They think that if they can sell them to Kachara Seth (Manoj Joshi) and pay off Tiwari, they can also become rich. But their neighbor once again steals the drugs from them. They then run into Anuradha and she tells them that the entire scam was hatched by Kabeera (the gangster from the first Hera Pheri) to get revenge on the trio, and that the only reason she went along with it was because they were holding her niece hostage (Anuradha's sister was Kabeera's gang member and part of the first movie's kidnapping plot). Their money was converted to diamonds to pay the ransom, but she fled with them once she discovered her niece had escaped.
In the end, all the guys end up in a circus show where they attempt to get hold of the diamonds. These are strewn all over the ground in public by a gorilla. Raju escapes with Pappu's cellphone and three antique guns with him, which are worth Rs. 5 to 6 crores, though he does not know about it. Thinking of all the trouble they have been in, he angrily tries to throw the guns into the river to get rid of their problems. Fortunately for him, the guns get stuck on a ledge. He tries to go down and throw them into the water. When Baburao and Shyam come to know about the worth of the gun from Pappu when he is arrested, they call Raju on Pappu's phone. The film ends with Raju attempting to get hold of the guns while his phone is ringing. On the other end, Shyam and Baburao anxiously wait for Raju to answer his phone.