Marmaduke, a Great Dane, lives in rural Kansas with his best friend, a cat named Carlos. His owners, Phil and Debbie Winslow, work for Bark Organic dog food. Phil is very strict, from Marmaduke's perspective. Phil is transferred to Orange County, California. Phil's boss, Don Twombly, wants to sell Bark Organic in nation-wide Petco stores. Phil and Don meet at the dog park to discuss Phil's assignment, an ad campaign to win over Petco. There, Marmaduke meets Mazie, who develops a crush on Marmaduke. He also meets Giuseppe, a Chinese Crested dog who is afraid of everything, and Raisin, a very smart but minute Dachshund.