Roddy (voice of HUGH JACKMAN) is a pampered pet mouse who lives the good life, especially when his human owners go on holiday, thus enabling him to party with various inanimate dolls and other toys. But his vacation is cut short when rowdy sewer rat Sid (voice of SHANE RICHIE) suddenly shows up and decides to make himself at home. Taken aback by Sid's looks and demeanor, Roddy tries to get rid of him by convincing the soccer hooligan that the toilet is a Jacuzzi, but the street smart rat turns the tables and instead flushes Roddy down the loo.
Which leads to him traveling through the plumbing and sewer system until he lands in an underground, miniaturized replica of London. There, he meets Rita (voice of KATE WINSLET), a tomboy rat who's in the middle of stealing a ruby back from Spike (voice of ANDY SERKIS) and Whitey (voice of BILL NIGHY), two rat goons who work for local villain Toad (voice of IAN McKELLEN).
Once the favored pet of Prince Charles before being unceremoniously replaced and then flushed into the sewers, Toad has a diabolical plan involving the World Cup finals, halftime, and humans' need to use the bathroom nearly all at once, thus ensuring an epic flood of water arriving at their city not long thereafter.
However, not only does Rita have the ruby he stole from her, but also an important cable needed to make his plan work. When Spike and Whitey can't get the job done, Toad then calls in Le Frog (voice of JEAN RENO) and his team of French, martial arts experienced amphibians.
While Rita and Roddy initially don't like or trust each other, they realize they must count on the other to get Roddy back home before his human owners return, and stop Sid before he can carry out his plan.