The film starts with an opening scene depicting Wes stealing some sort of equipment from the strongly guarded headquarters of Team Snagem, and then proceeding to flee with an Espeon and Umbreon as the base explodes. After riding on a strange one-wheeled motorcycle for a while, Wes stops at the dilapidated gas station of Outskirt Stand. Wes battles Rider Willie, who tells him about Phenac City after he is defeated.
Upon reaching the new location, a pair of shady people are just leaving the city with a noisy, wriggling sack in tow. Once they see that they've been caught, one of the goons, Folly, starts a battle with Wes. After defeat, both people get away, leaving the sack unattended. A girl name Rui emerges from the bag after some trouble undoing the knot, and claim to have seen the kidnappers use some kind of strange looking Pokémon. Rui becomes Wes' partner and both go to find the Mayor to clear things up. A strange man bumps into Wes as he leaves the Mayor's office, predicting that he will see Wes again sometime in the future. Wes and Rui then enter the house as the girl proceeds to alert the Mayor of weird Pokémon that have a dark aura and attack humans. The Mayor assures the team that he will look into this case, and suggests going to the city's Stadium. At the doorway of the Stadium, some Snagem members recognize Wes as the traitor who blew up their base. A battle with one of them ensues, and upon defeat, Rui tells Wes that she doesn't care about the past, but she does encourage buying some Poké Balls for future use. After this scene, Rui becomes Wes' permanent partner, and will follow him throughout the length of the film.
Then, after purchasing some Poké Balls at Outskirt Stand, Wes returns to Phenac City, only to find it taken over by some thugs. Wes tries to rescue the Mayor, but finding the decked-out Miror B. and his mischievous friends in his wake. Rui identifies the first Shadow Pokémon available for capture after entering a battle with Miror B.'s underlings, Folly and Trudly. After beating both in a battle, and/or capturing the Shadow Pokémon, Wes tries to leave the city for Pyrite Town, but is waylaid by brightly clad goons at each exit. Each has a Shadow Pokémon, but upon defeat of one will cue the others to leave.
From this point, Wes and Rui will journey all across the Orre region, battling Trainers, snagging Shadow Pokémon, and uncovering the disastrous plan of the secret organization, Cipher. This shady group and its ambitious admins are the creators of Shadow Pokémon, closing their hearts to strengthen their stats. The player eventually learns how to reverse the effects of this process, and must capture all of Cipher's Shadow Pokémon to thwart the evil mastermind behind it all. After defeating Miror B in Pyrite Cave, Dakim in Mt. Battle, Venus in The Under and Ein in the Shadow Pokémon Lab, Wes goes to Realgam Tower; after defeating the Admins again, Gonzap comes out and reveals that Cipher gave Team Snagem the Snag Machines; and that Snagem gave the Pokémon to Cipher, who created Shadow Pokémon; meaning that this was all one master plan hatched by Cipher. After defeating Snagem, Nascour—the boss of Cipher—is defeated by Wes. Afterwards, it is revealed that Phenac City's mayor Es Cade is actually Evice, the true boss of Cipher. After he is defeated he tries to escape; however, fortunately, a Ho-Oh uses Sacred Fire to stop him, saving the day.
Even with the true leader under arrest, there is still a post-ending to be completed. Secc, from the Kids Grid, emails Wes information about some interesting characters who end up telling Wes about some points of interest. Eventually, the Snagem Hideout becomes available for exploration, the Shadow Pokémon Laboratory gets some Cipher refugees to battle, and a hidden Stadium in the Under is brought to Wes' attention. Lastly, after all the Shadow Pokémon are snagged, Wes will be notified of a Trainer that is attacking people with another Shadow Pokémon, who supposedly looks just like him. After the copy's defeat, there are still Colosseum battles to be won and a Ho-Oh to be obtained in Battle Mode.
- Justin Timberlake as Wes
- Danielle Panabaker as Rui
- Nick Nolte as Evice
- Nicholas D'Agosto as Nascour
- Arnold Schwarzengger as Duking
- Bobby Campo as Silva
- Josh Hutcherson as Nett
- Matthew Knight as Bitt
- Georgie Henley as Megg
- Ian McKellen as Eagun
- Amanda Righetti as Ferma
- Amanda Seyfried as Reath
- Mark Wahlberg as Miror B.
- Chris Hewsworth as Folly
- Liam Hemsworth as Trudly
- Sarah Silverman as Ancha
- Helen Mirren as Beluh
- Scott Speedman as Willie
- Rupert Grint as Justy
- Joel Courtney as Cail
- Vanessa Redgrave as Fateen
- Michael Keaton as Chief Sherles
- Patrick Dempsey as Officer Johnson
- Colin Ford as Secc
- Daniel Radcliffe as Vander
- Alex Pettyfer as Dakim
- Sienna Miller as Venus
- Chris Pine as Ein
- Shantel VanSanten as Marcia
- Danielle Panabaker will wear a orange pigtail wig for her role
- Nicholas D'Agosto will wear a gray wig for his role
- Amanda Righetti will wear a purple wig for her role
- Amanda Seyfried will wear a red short wig for her role
- Rupert Grint will wear a black wig for his role
- Daniel Radcliffe will wear a red wig for his role
- Alex Pettyfer will wear a curly red hair for his role
- Bobby Campo will wear a dirty blonde wing for his role
It will distributed by Columbia Pictures and Screen Gems with Pikachu the Movie