Marmaduke, a spirited teenage Great Dane, resides in the picturesque countryside of Kansas with a feline companion named Carlos. His owner, Phil Winslow, is quite the disciplinarian, at least from Marmaduke's point of view. When Carlos unveils a surprising piece of news—Phil has plans to relocate them to Orange County—their lives are set on a new trajectory. The move from their humble Kansas home to a vibrant California neighborhood introduces them to a plethora of new experiences.
Upon arriving in their new abode, Phil is eager to impress his boss, Don Twombly, who aims to catapult Bark Organic dog food into every Petco store across the nation. A chance meeting at the local dog park becomes crucial as Phil discusses a tantalizing advertising campaign aimed at winning over Petco’s executives. Here, Marmaduke encounters Mazie, a delightful pup who quickly develops a crush on him. He also befriends Giuseppe, a timid Chinese Crested with a penchant for worrying, and Raisin, a clever yet diminutive Dachshund.
Marmaduke’s world takes a twist when he catches sight of a stunning Rough Collie named Jezebel. She’s linked romantically to Bosco, a menacing Beauceron with two mischievous Miniature Pinschers, Thunder and Lightning, in tow. Intimidated by Bosco's ferocious demeanor, Marmaduke is hesitant to engage in any fights. However, things transit into chaos when he and his newfound mutt friends crash Bosco's exclusive party for pedigreed dogs, only to be scared off by his intimidating presence.
Desperate to impress Jezebel, Marmaduke seeks help from Mazie. To her surprise, she learns the dog he’s after isn’t her but rather the beautiful Jezebel. Using clever tactics, Marmaduke stages a faux fight with Carlos in the park to boost his street cred. This escalates to Marmaduke entering a dog-surfing contest — a publicity stunt orchestrated by Phil — where, against all odds, he defeats the reigning champion Bosco, leading to a showdown that shocks the attending Petco executives.
In a bid to correct his unruly behavior, Phil hires a dog trainer named Anton, though initial efforts prove fruitless. Eventually, Marmaduke manages to impress Jezebel by taking her on a romantic outing, under the watchful eye of Mazie, who believes it’s her date instead. Back at home, a party thrown by Marmaduke spirals out of control when Bosco crashes it, leading to Marmaduke’s downfall as he gets exposed and loses both his friends and his home.
Feeling desolate, Marmaduke finds solace in the companionship of Chupadogra, a wise, elderly English Mastiff known for his fearsome reputation in Orange County. Chupadogra, who has endured heartbreak himself, encourages Marmaduke to return home before it’s too late. However, in a twist of fate, Marmaduke becomes lost, prompting a frantic search by the Winslows and Mazie, who discover him at the same time.
In a dramatic turn of events, Mazie faces peril when she falls into an underground rainwater conduit. In a heroic moment, Marmaduke leaps to her aid. As rescue efforts unfold, Phil reveals the depth of his commitment to Marmaduke. Their bond strengthens as Marmaduke is ultimately saved, an event that unexpectedly goes viral, resonating with thousands online, which revitalizes Phil's career.
As life returns to normal, plans to relocate back to Kansas are overturned when the entire Winslow family chooses to remain in California. Taking a stand, Marmaduke addresses the dog park community, advocating for equality regardless of their breed, which takes down Bosco's reign of terror. The film culminates with a joyous finale where Marmaduke, Jezebel, Mazie, Giuseppe, Raisin, and others joyfully dance and sing "What I Like About You", which cleverly serves as a backdrop for Phil and Don’s next commercial venture. In the end, Marmaduke finds friendship and love with Mazie while also solidifying his friendships with Jezebel, culminating in a delightful moment as he mischievously disrupts Phil and Debbie’s night with a classic doggy fart.
