Some time after the Mousekewitz's have settled in America, they find that they are still having problems with the threat of cats. That makes them eager to try another home out in the west, where they are promised that mice and cats live in peace. Unfortunately, the one making this claim is an oily con artist named Cat R. Waul who is intent on his own sinister plan. Unaware of this, the Mousekewitz's begin their journey west, while their true cat friend, Tiger, follows intent on following his girlfriend gone in the same direction.
A legendary dog trainer believes he can transform Marmaduke from an undisciplined, but lovable dog, into the first Great Dane to win the World Dog Championship.