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 has forgotten her birthday.
In Paris, Gargamel is now a celebrity, amazing people with his sorcery, but he is running low on the Smurf essence that gives him his magic powers. With his new creations, evil Smurf-like creatures called the Naughties, named Vexy and Hackus, Gargamel creates a portal to Smurf Village by using the Eiffel Tower as a conduit so that he can kidnap Smurfette as revenge on The Smurfs for defeating him in the first movie and, through her, obtain Papa’s secret formula for creating Smurfs. However, Gargamel is too large to go through the portal, so he sends Vexy through it to kidnap Smurfette.
The Smurfs witness the abduction of Smurfette and inform Papa, who uses his magic to create crystals that allow several of his Smurfs to travel directly to the residence of their human allies, Patrick and Grace Winslow, in New York City in order to seek his help to rescue Smurfette. Papa originally intends for Brainy, Hefty and Gutsy to use the crystals, but through an accident, Clumsy, Grouchy and Vanity use them instead. The Smurfs arrive in Patrick and Graces’s apartment right after the celebration of their son Blue’s fourth birthday where they meet Patrick’s stepfather, Victor Doyle, who is a constant embarrassment to Patrick. The Smurfs soon discover Gargamel is in Paris and set off with the Winslows to find him.
Upon arrival in Paris, Patrick and Grace work with Victor to distract Gargamel during one of his performances, while the Smurfs sneak backstage in Gargamel’s dressing room to look for Smurfette, only to discover what Gargamel is planning. At the same time, Smurfette escapes from her prison, and Vexy and 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. Smurfette still refuses to give Gargamel the formula until she sees the Naughties are dying due to a lack of Smurf essence. Faced without an alternative to save them, Smurfette writes the formula down and Gargamel uses it to turn the Naughties into real Smurfs. Immediately after they become Smurfs, Gargamel puts them into his Smurfalator 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 large-sized dragon wand. Patrick and Victor arrive just in time to destroy the Smurfalator together, causing an explosion of Smurf essence that destroys the written formula and frees the Smurfs from their cages. Everyone is blasted out of Gargamel’s lair through a sewer hole where Patrick and Victor reunite with Grace and Blue. Gargamel reappears out of the sewer hole only to be blasted away by Smurfette with her new wand. He then falls onto the Notre Dame Cathedral, where he accidentally brings a stone African wild dog to life, which then throws him to the top of the Eiffel Tower where fireworks are then set off, sending him into the air. The Smurfs bid farewell to the Winslows, then return home with Vexy and Hackus to celebrate Smurfette’s birthday.
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.