Whilst in Central City, orphans Andi (Emma Roberts) and Bruce (Jake T. Austin) manage to sell a rock in a box to a pawn shop for twenty-seven dollars, in order to feed their dog, Friday. However, they are quickly caught and marched off to the police station, where their social worker, Bernie Wilkins (Don Cheadle) picks them up and takes them back to their foster parents, Lois and Carl Scudder (Lisa Kudrow and Kevin Dillon, respectively), who appear not to care for either Andi or Bruce. When the two demand to know where their foster children have been, Bernie covers for them, telling them that it was his fault they were late. Despite his sympathies towards the two siblings, he warns them that they are playing a dangerous game by deliberately getting into trouble in order to escape Carl and Lois, since they could get fostered separately, something that both orphans are desperate to avoid. During Bernie's visit, Friday returns home, and Bruce quickly bustles Bernie out of the door, since Friday's presence is to be kept secret.
The next morning, Andi and Bruce are horrified to find that Friday has snuck downstairs and is dangerously close to Lois discovering him. After a close call, Andi and Bruce rush Friday upstairs to their bedroom, where Friday promptly goes looking for food again, only to be caught by Animal Control. Sick with worry, Andi and Bruce go into a local pet shop to ask if anybody has seen him; there, they meet Dave, (Johnny Simmons) and Heather, (Kyla Pratt) who advise them to check the Pound. Upon learning that Friday is indeed in the Pound but they cannot claim him unless their parents are there, Andi pays for Friday's return and suggests to Bruce that they find Friday a new home, since he deserves a real home. Whilst walking home, they find a gang of youths breaking into an abandoned hotel, only to flee when the police arrive; since Andi and Bruce are the only ones left at the scene, Andi urges Bruce to hide in the hotel. Whilst looking for Friday, who had curiously begun to explore the hotel, they find a tiny Boston Terrier and an English Mastiff, whom they name Georgia and Lenny, respectively. Confident that the three dogs get along, Andi and Bruce leave Friday at the hotel for the night.
The next morning, Andi and Bruce return to the hotel, with Andi warning her younger brother to not get too attached to the two stray dogs. Whilst Bruce stays at the hotel to keep the dogs quiet and creates a machine that allows them to play 'Fetch' whenever they like, Andi heads to the pet shop to get some food for the strays, claiming that her parents rescue dogs, prompting Dave to ask her to take in three dogs-Shep, Romeo and Cooper-who nobody seems to want to adopt. Andi begrudgingly agrees. Upon arriving at the hotel, Dave and Heather immediately agree to help the two siblings out. With six dogs to now look after, the friends set about trying to get the hotel in a decent enough state to suit the dogs needs, including building running machines, automatic feeders and a car simulator. Whilst they're working, a local boy named Mark offers his assistance as more stray dogs begin to occupy the hotel.
Back at the Scudder's household, Bernie eagerly tells them of a couple of new foster parents he's found Andi and Bruce. However, their new foster parents live hours away, the two turn the offer down in order to continue looking after the dogs, much to Bernie's bewilderment. Whilst thinking over her decision, Dave invites Andi to a party, and she happily accepts; Mark, meanwhile, makes various efforts to gain Heather's attention. Whilst everyone else is at the party, Bruce is caught stealing a hairdryer from Lois, and is immediately interrogated by his foster parents; meanwhile, Andi bumps into an old acquaintance who accidentally notifies everyone that Andi is an orphan. Bruce manages to escape his house, only to find the hotel in a state; Lois and Carl follow him and the police are called-the dogs are quickly caught and sent to the Pound, much to Bruce's despair. When Lois and Carl refuse to take Andi and Bruce back, Bernie is forced to send them to separate foster homes.
With all of the dogs to be put down the next day, Friday manages to escape his captivity and rushes over to find Dave, Heather and Mark, who in turn find Andi. They all hurry over to find Bruce. Meanwhile, Bernie decides to look around the hotel, where he finds a beagle who managed to avoid capture, and marvels at the creations Bruce made. Andi and Bruce manage to break into the Pound and release the dogs, where Bruce entices the hoard of dogs to follow Dave's van through the city with sausages. The strange event attracts the attention of the police, who follow the dogs to the hotel, where Bernie is waiting. With a large crowd gathered outside, Bernie begins to list the names of the dogs who live at the hotel, winning the public's hearts.
As people eagerly explore the hotel, Bernie reveals to an overjoyed Andi and Bruce that he and his wife have decided to adopt them. The hotel re-opens as a grand 'Hotel For Dogs', where people can either adopt strays or board their dogs. Although Lois and Carl are invited to provide the entertainment for the 'Dog Lounge,' the dogs quickly grow bored with their act, and the two are sent offstage in disgrace. Meanwhile, Andi, Bruce and Friday begin to happily settle into their new family.