In preparation for her birthday celebration, the Smurfs read the story of Smurfette, how she was created by Gargamel to destroy them, only for Papa Smurf to rescue her and turn her fully into a Smurf. Meanwhile, she is having nightmares about reverting to her original form and betraying her fellow Smurfs by turning them over to Gargamel. The Smurfs are preparing a surprise party, but as Smurfette tries to find out what her fellow Smurfs are planning, none of them are saying a word. She takes this to mean that everyone forgot her birthday.
In France, Gargamel is now a celebrity, amazing people with his sorcery, but he sees that he is running low on the Smurf essence that gives him his magic powers. With his new creations, evil Smurf-like creatures called Naughties Vexy and Hackus, Gargamel plans on opening a portal to the Smurf village by using the Eiffel Tower as a conduit so that he can kidnap Smurfette and, through her, get Papa Smurf's secret formula for creating Smurfs. However, as the portal he created is not big enough for him to go through, Gargamel takes Vexy and sends her through to the portal to grab Smurfette and bring her to Paris.
The Smurfs witness the abduction of Smurfette and inform Papa Smurf, who then uses his magic to create crystals that would allow several of his Smurfs to travel directly to Patrick Winslow's residence in New York City in order to get his help to rescue Smurfette. Papa originally intended for Brainy, Hefty, and Gutsy to use the crystals, but instead through an accident Clumsy, Grouchy and Vanity use them. Papa and the three Smurfs arrive in the apartment right after the celebration of Blue's fourth birthday where they meet both the Winslows' young boy and Patrick's stepfather Victor Doyle, a man who is a constant embarrassment to Patrick. The Smurfs soon discover where Gargamel is, and so they and the Winslows set off for Paris in order to find him.
After their arrival in Paris, Patrick and his wife Grace work together with Victor to distract Gargamel during one of his performances while the Smurfs sneak backstage in order to find Smurfette, only to discover what Gargamel is planning. At the same time, Smurfette escapes from the prison and Vexy and her partner Hackus chase after her. Upon her return to Gargamel's hotel suite with the Naughties, Gargamel presents her with a tiny dragon wand as a feigned act of kindness, reminding her that he was her creator and that Papa Smurf had no interest in her.
Smurfette still refuses to give Gargamel the formula to turn a naughty into a smurf until she sees that the Naughties are dying due to a lack of Smurf essence. Faced without an alternative to save them, Smurfette quickly writes the formula down and Gargamel uses it to turn the Naughties into real Smurfs. Immediately after they become Smurfs, the evil wizard puts them into his Smurf-a-lator so he can carry out the rest of his plan.
Meanwhile, Patrick, Victor, and the Smurfs work together to rescue Smurfette. The Smurfs are soon captured and put into the Smurfalator, powering Gargamel's "La Wanda" (a large-sized dragon wand). Patrick and Victor arrive just in time to destroy the Smurf-a-lator, causing the naughty-to-smurf formula to be destroyed in blue pixie dust that in turn vanquishes the secret formula. Gargamel has gained enough power to use his new wand against the Smurfs and their allies. Vexy and Hackus team up with the Smurfs against their former master and use the new wand to blast him away. He then falls onto the Notre Dame Cathedral where he accidentally brings a stone vulture to life which then throws him to the top of the Eiffel Tower where fireworks then set off, sending him in the air. Vexy and Hackus, the two new Smurfs, bid farewell to the Winslows and return home with the rest of the Smurfs.
In two post-credit sequences, Gargamel and Azrael are pulled into the portal, sending them back to their castle, and they later have a fight.
Live action actors
- Hank Azaria as Gargamel
- Neil Patrick Harris as Patrick Winslow
- Brendan Gleeson as Victor Doyle, Patrick's stepfather
- Jayma Mays as Grace Winslow, Patrick's wife
- Jacob Tremblay as Blue Winslow, Patrick and Grace's son
- Nancy O'Dell as herself, a television interviewer
- Katy Perry as Smurfette
- Christina Ricci as Vexy, a smart and mischievous Smurf-like creature called a "Naughty" created by Gargamel 
- J. B. Smoove as Hackus, a funny and physical Smurf-like creature called a "Naughty" created by Gargamel
- Jonathan Winters as Papa Smurf
- Fred Armisen as Brainy Smurf
- Alan Cumming as Gutsy Smurf
- Anton Yelchin as Clumsy Smurf
- George Lopez as Grouchy Smurf
- John Oliver as Vanity Smurf
- Mario Lopez as Social Smurf
- Jimmy Kimmel as Passive Aggressive Smurf
- Frank Welker as Azrael
- Tom Kane as Narrator Smurf
- Paul Reubens as Jokey Smurf
- B. J. Novak as Baker Smurf
- Shaquille O'Neal as Smooth Smurf
- Shaun White as Clueless Smurf
- Jeff Foxworthy as Handy Smurf
- Gary Basaraba as Hefty Smurf
- Adam Wylie as Panicky Smurf
- Joel McCrary as Farmer Smurf
- Kenan Thompson as Greedy Smurf
- John Kassir as Crazy Smurf
- Kevin Lee as Party Planner Smurf
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