A pampered Jack Russell Terrier named Max lives with his owner Katie in a Manhattan apartment. While she is at work during the day, he hangs out with other pets in the building: tabby cat Chloe, pug Mel, dachshund Buddy, and budgerigar Sweet Pea. One day, Katie adopts Duke, a large Newfoundland mix from the pound, leaving Max jealous because of her divided focus on Duke. Enraged by Max's attitude towards him, Duke tries to abandon Max in an alley, but they are both attacked by cats led by Sphynx cat Ozone who steals both dogs' collars and leaves them to be caught by Animal Control. Duke fears that he will be killed if he goes back to the pound. When Gidget, a white Pomeranian who has a crush on Max, discovers that he is missing, she decides to find him.

Max and Duke are rescued by a white rabbit named Snowball, the leader of "The Flushed Pets"—a cult of feral sewer-dwelling animals who hate humans because their owners mistreated and abandoned them. After Max and Duke pretend to despise humans as much as they do by saying they killed their owners, the Flushed Pets invite them to join. Before they can prove their loyalty by allowing a one-fanged viper to bite them, Snowball learns from the cats that Max and Duke are pets. The two dogs escape the sewers and board a ferry to Brooklyn, inadvertently killing the viper in the process. Snowball vows to kill them and leads the Flushed Pets after them.

Meanwhile, Gidget recruits a red-tailed hawk named Tiberius to find Max, but he mistakenly locates Ozone, whom Gidget coerces into telling what he knows about the dogs. They then enlist Mel, Buddy, Chloe, guinea pig Norman and Sweet Pea. On the way, they meet Pops, an old Basset Hound who helps Gidget and the pets find Max. Gidget and her team encounter Snowball, who vows to kill them as well, and Norman is captured as the rest of Gidget's team flees.

In the meantime, Max and Duke raid a sausage factory for food. While there, Duke tells Max about his previous owner, Fred, an elderly man who adopted him as a puppy and loved spending time with him. One day, Duke got lost while chasing a butterfly and was caught by Animal Control, but Fred never came to claim him. Max convinces him to visit Fred's house in a nearby neighborhood, confident Fred will still love him and take him back. When they arrive at Fred's house, they learn from the resident cat Reginald that Fred has died. Heartbroken, Duke accuses Max of attempting to get rid of him and barks at the new homeowners who have just returned to the house and called Animal Control. The handlers catch Max, but Duke interferes long enough for Max to escape and ends up being captured instead.

While trying to rescue Duke as he follows the Animal Control van, Max is attacked by Snowball who tries to kill him. However, when his gang is captured, Snowball realizes that he and Max must work together to rescue them. They drive a city bus into the van on the Brooklyn Bridge, stopping traffic. The Flushed Pets encircle Max, unaware of his partnership with Snowball, but Gidget and her team save him. Upon seeing Gidget using her kung-fu fighting skills, Max starts to fall in love with her. The van gets stuck in scaffolding and the Flushed Pets escape. As soon as Max gets the keys to Duke's cage, the van plummets into the East River with him inside. Max is unable to free Duke, so Snowball jumps into the river to retrieve the keys, allowing them to escape the sinking van.

The entire group returns to the apartment block by pig-driven taxi. Max expresses his love for Gidget, who returns his affection. Snowball and the Flushed Pets then come up with a new plan to annihilate all humans, but a woman and her daughter named Molly arrives and adopts Snowball and the remaining Flushed Pets return to the sewers. At first, Snowball resists, but gives in and lets himself become a domesticated pet. Snowball soon goes home with Molly and her mother while the other pets return to their homes and embrace their owners, and Max and Duke finally reunite with Katie, sparking a true friendship as brothers. In a post-credits scene, Buddy and Mel show up in costume at a party in poodle Leonard's apartment, hosted by a now-friendlier Snowball.

The Minions need to raise $20 to purchase an as seen on TV banana blender, so they take up lawn mowing at an old folks home, with hilarious antics.

Norman, a lost guinea pig, wanders in the pipe through apartments in New York, and his main recreation during his adventure is to see how the apartment residents live - with popcorn and remote controls.

The Sausages live happily in Weenie Ville. Once, a sausage called Timmy is so sacred of diving, which results that he is teased as a "weenie". Leaving the diving pool, Timmy sits on a bench beside, sighing. Frank, the mayor of Weenie Ville, happens to see the desperate Timmy, so he takes Timmy, singing and traveling around Weenie Ville to see the fantastic life of sausages to comfort him. In the end, Timmy dares to dive from a higher place and he is quite proud about himself.

Sometime after the events of the first film, Max and Duke's owner, Katie, gets married to a man named Chuck and have a son, Liam, whom Max disapproves of at first due to his rough play but eventually softens up to him. Later, Max's overprotective feelings for Liam develop into an itch which prompts Katie to get him a dog cone from the veterinarian in an effort to lower his symptoms. Max's luck changes when Duke reveals that the family is going on a road trip outside of the city.

When Max and Duke's family reaches a farm owned by Chuck's uncle, Max grows unaccustomed to the farm's ways, including local sheepdog Rooster. After an incident with the farm's sheep, Rooster takes Max out to find one of the missing sheep that ran away. Rooster's teaching and encouragement to Max about acting unafraid prompts Max to successfully retrieve the sheep. Rooster allows Max to stay with him overnight as a result. Before departure, Rooster also gives Max one of his handkerchiefs as a souvenir.

Before Max left, he had entrusted his favorite toy, Busy Bee, to Gidget. Unfortunately, Gidget loses Busy Bee in a cat-infested apartment owned by a cat lady. She receives cat lessons from Chloe, Mel, Buddy, and Sweet Pea in order to sneak in the apartment easier. With the help of Norman, she successfully retrieves Busy Bee and unintentionally gets hailed as the "queen of cats".

Meanwhile, Chloe and Snowball meet Shih Tzu Daisy, who explains that she needs Snowball, who dreams of being a superhero, to assist her with rescuing a White tiger cub named Hu, who can understand pets, but can't talk to them. While on flight back to the city, Daisy encountered him being held captive by an abusive circus owner named Sergei. Daisy and Snowball sneak in and find the circus Hu is in. With much difficulty from Sergei's black wolves, they free Hu from the circus. However, in the heat of the escape, Daisy accidentally drops her flower clip, which the wolves use to track her down.

She and Snowball take him to Pops' apartment first. Pops reluctantly lets Hu live there at first, but due to his destruction of the apartment afterwards, Hu is kicked out and relocated in Max and Duke's apartment. Around the same time, the family returns from the trip. Sergei and his wolves track Daisy down and capture both Hu and Daisy. Sergei escapes in his train moving for the circus in which Snowball, Max, and Norman pursue while contacting Gidget for assistance in the chase. Gidget and the cats take their owner off in her car, in pursuit of the train.

Max and Snowball defeat the wolves and Sergei's pet monkey, while freeing Hu and Daisy respectively. Max, using his newfound bravery Rooster gave him, successfully infiltrates the train locomotive Sergei is in. The rest of the animals go and kick him out of the train. But before they are shot by Sergei, Gidget, along with the cat lady, Chloe, Mel, Buddy, Duke, and Sweet Pea knock him out with her car and offers the animals a ride back home. Life resumes normally, with Max and Duke's family saying goodbye to Liam as he enters his first day of preschool while Hu takes up residence in his new home with the cat lady and Snowball becomes New York City's local superhero.

In a mid-credits scene, Snowball raps to "Panda", which only lasts briefly before his owner, Molly, comes into the room he is in.

When Max is kidnapped by an army of squirrels, Super Gidget is the only one who can save him. It turns out that Max's captor is a flea with the power of mind control. Gidget must use her pluckiness, strength and smarts to save her one true love - until it turns out it was all just a dream.

When Margo, Agnes and Edith return from Badger Scout camp, three of the Minions are entranced by the girls' merit badges. Their own attempt at scout camp results in attracting a bear, eating poison berries and eventually blowing up a dam, creating a massive flood. But, when they arrive back home, the girls share their badges, encouraging the rest of the Minions to try their hand at scouting.