The movie starts with George swinging around town, & he picks up the newspaper. He reads it when he gets home & finds out that the great magician Piccadilly's holding an act with an elephant called Kayla. It sounds interesting to George so he wakes up Ted , & he tries to show Ted the news, but Ted's late for a meeting with Mr. Bloomsberry.
When Ted gets to the museum he prepares reasons as to why he would be a good candidate to take over the museum for Mr. Bloomsberry who's retiring. Mr. Bloomsberry however, says that Ted's the only candidate because he couldn't imagine leaving not even Junior (the main antagonist from the 1st film) to own the museum (he's now a cashier at a parking lot). The only stipulation's Ted has to write a presentation on what his vision of what the museum would look like; to be delivered in 1 week, to the Board of Directors. However Ted's scared of the Board of Directors.
As Ted's in his office writing his charts, Maggie tells him that his loved needs more attention: her, George, etc. George comes in & tries to show Ted the poster with Kayla (indicating Piccadilly's act). Ted says he understands what Maggie's saying & decided to take George to the magic show. During 1 of Piccadilly's magic tricks, Kayla disappears, & George goes looking for her. He finds Kayla in the basement of the theatre, starts playing with her & they stumble upon the exit for the building. Piccadilly comes in & can't find Kayla so he calls for security, the head of which is Danno Wolfe (this film's main antagonist) who's assisted by Mrs. Fisher. Danno questions Ted & gets suspicious about him & George. Meanwhile, George & Kayla make their way to Ted's apartment where they see news coverage of Kayla's original home in California with her brother Tonga & her sister Layla.
Ted returns home to find George & Kayla in their apartment. He decides to return to the theatre with George & Kayla but along the way loses them when George sees a train advertisement for the "California Express". Ted reaches them at the train, but can't get them out of the boxcar before it leaves the station. They are headed west & Ted gets nervous when the train doesn't even stop in St. Louis & his cell phone's battery has died. Meanwhile, a cryptic message from a monkey Danno thinks speaks Chinese leads him to believe that George & Ted have kidnapped the elephant. He begins attempting to find them.
Back on the train, George opens the door of the boxcar but Ted falls out while trying to catch the wind-blown pages of his presentation. Ted makes his way to a small train station with a stationmaster who offers to charge the cell phone (which broke when he fell). Ted uses what little change he has to call Piccadilly, but doesn't manage to complete the call which makes Danno even more certain that Ted & George have kidnapped Kayla. Ted uses the stationmaster's motorcycle to catch up with George & Kayla, & reboards the train. He leaves his cell phone in Humbleton with the stationmaster who tries to use the phone to tell Piccadilly that Kayla's okay but the phone breaks. Mrs. Fisher traced the call which allowed Danno to find his way the Humbleton station.
Ted, George, & Kayla continue on the train for the next stop in Grand Junction with Danno on their heels. The movement of Kayla, however, causes the boxcar to separate from the rest of the train, & they head away from the rest of the train. It finally stops, & they get off in search of a road to find help. A man in a flatbed truck stops & picks them up. Ted thinks they are going east, but they continue to travel west once again. Meanwhile, Piccadilly's interviewed by Hark Hanson, & he reveals pictures of George & Ted as the kidnappers of Kayla. Ted wakes up after a night's sleep in the back of the truck & realizes they have been heading the wrong way. He gets them off the truck & attempts to head back east again.
They come across a farmer named Dan & his child named Anna, with whom they spend the night. The next morning, Ted picks up the newspaper & finds out New York thinks they're kidnappers. He also reads about Kayla's family. Ted wants to return Kayla to Piccadilly, but George & Anna disagree. Ted changes his mind the next morning but before they leave for Kayla's home, Danno shows up in a helicopter. After the pig throws Danno into a rain barrel, Kayla scares the pilot into flying away. While they are thus distracted, George & company escape using a hollowed out school bus & finally make their way to the park where Tango and Layla are happy to see her. Danno shows up again & arrests George & Ted & captures Kayla. They fly back to the city, but after George gets the handcuff keys from Danno, they all escape by jumping out of the plane. They make it back to Piccadilly & everything's fine, except that Danno has followed them once again. Kayla subdues him & throws him onto the stage's trapdoor which Piccadilly opens, dropping Danno onto the mattress below.
George & Maggie watch Ted give his report to the Board of Directors. He's initially flustered because the past week's adventures prevented him from preparing his presentation. Once George comes in the room, Ted improvises a speech saying that friends are more important than work & proposes several ideas for the museum based on that idea (Father/Son Day for example). The Board's impressed & approves his appointment.
- Frank Welker as George/Duck/Cow
- Jeff Bennett as Ted (The Man With the Yellow Hat) (replacing Will Ferrell)
- Fred Tatasciore as Mr. Bloomsberry (replacing Dick Van Dyke)
- Nicki Bryar as Maggie (replacing Drew Barrymore)/Teenage Boy
- Ed O'Ross as Ivan
- Amy Hill as Flower Pot Lady/Irate Woman
- Tim Curry as Piccadilly
- Catherine Taber as Tina
- Jamie Kennedy as Danno Wolfe
- Matt Lauer as Hark Hanson
- Jerry Lewis as the Humbleton Stationmaster
- Cree Summer as Mrs. Fisher/Cargo Pilot/Young Girl
- Jeff McNeal as Kayla/Hog/Tonga/Layla
- Clint Howard as Farmer Dan
- Trupti Potdukhe as Anna
- Phil LaMarr as Animal Park Attendant
- Carlos Alazraqui as Conductor/Newspaper Vendor
The soundtrack features the hit "California Sun" performed by Brian Wilson as well as all new songs by Carbon Leaf, a special title track recorded by 429 Records' artist Jackie Greene, & an original score by Heitor Pereira. The soundtrack was released on March 2, 2010.
- "Life Less Ordinary" – Carbon Leaf
- "The Friendship" – Carbon Leaf
- "California Sun" – Brian Wilson
- "On A Roll" – Carbon Leaf
- "Heart Of The Day" – Carbon Leaf
- "Let Your Troubles Roll By" – Carbon Leaf
- "Walking In The Sun" – Carbon Leaf
- "Follow That Monkey" – Jackie Greene
- "Moon Man" – Heitor Pereira
- "Going East" – Heitor Pereira
- "Giving A Hand" – Heitor Pereira
- "Zoo" – Heitor Pereira
- "Friendship" – Heitor Pereira
The film was released in the United States on March 2, 2010 as a direct-to-DVD release. The film was broadcast on PBS, as a special for a few days, around Thanksgiving 2011.
A sequel, titled Curious George 3: Back to the Jungle, was released directly to DVD on June 23, 2015.