Trouble is a pampered dog, living the good life in a mansion with his wealthy, elderly owner, Mrs. Sarah Vanderwhoozie, under the care of her loyal butler, James, and famed animal trainer Cesar Millan.

While discarding her belongings and planning to sell other priceless items, they accidentally and unknowingly get rid of Trouble, whom they show instant dislike and apathy.

Realizing that Trouble is missing, they hire Thurman Sanchez, an Ace Ventura-esque but expert animal tracker, to find him before the deadline.

Having made it out of the truck carrying away his owner's belongings, and after learning the truth about her death, Trouble accidentally messes up a group of red squirrels' nut storage in their tree.

In the city, Trouble meets a stray dog named Rousey while trying to get a meal from a meat truck, which results in a chase through a restaurant owned by famed chef Ludo Lefebvre; a wannabe-singer pizza delivery girl named Zoe Bell also loses one of her pizzas.

However, one day, after saving her owners' child from a traffic collision, they mistook her heroic behavior for aggression and dumped her at the pound, which explains Rousey's distrust of humans.

Returning Trouble to Claire and Norbert at the mansion, Thurman secretly vows retaliation with the squirrels' help after the twins refuse to pay him as promised.

Having misled Mr. Macbain that they bonded with Trouble, Claire and Norbert are about to claim their inheritance when Zoe suddenly arrives, revealing what really happened.

Still wanting his money, Thurman summons the squirrels to hold Trouble for ransom, until Snoop, Otis, and Caramel enter, having followed Rousey; a battle ensues.

[1] New York Times writer Chris Azzopardi wrote, "Home is at the center of Dog Gone Trouble, about a lost pooch whose owner has just died.

"[5] However, Jennifer Green of Common Sense Media had a more favorable response, writing, "Animated dog films can feel a dime a dozen, but this one might stand out thanks to its diverse cast, star cameos, and sly humor.