After witnessing the unintentional death of a hooker by the mayor, two rats named Mike and Phil attend a party where it is discovered that Phil has never made babies while Mike raises his newborn daughter Rebecca as she grows into an adult over the course of the party. As Phil falls in love with Rebecca, he learns that he ate rat poison and spends his final moments finally having sex with Rebecca raising their son Phil Jr. Meanwhile two police horses (voiced by Paul Scheer and Matt Walsh) discuss a friend who has become a race horse; also two bed bugs (voiced by Mark Duplass and Rob Corddry) move into the mayor's pubic hair and talk about one of their divorce and subsequent midlife crisis.

As the mayor deals with a blackmailer who took pictures of him with the hooker, unaware that one of his goons is an undercover detective, a golf ball hits a sleeping Phil's nest as he believes it to be an egg he laid. He joins his friend Mike and Mike's wife Megan to their son Jacob's Little Flyers Club where Mike is challenged to race to the Green Lady with the Ice Cream Thingy by Jerry, a pigeon from New Jersey (voiced by Nick Kroll). Meanwhile two caterpillars named Alan and Brian (voiced by Ike Barinholtz and Zach Woods) respectively, deal with one of their metamorphoses.

As the mayor's wife is having an affair with her husband's opponent in the upcoming mayoral campaign, her pet cats Mike and Phil discuss their plans for the day when they are interrupted by an alley cat at the window named Alex (voice by Eric André). Mike and Phil let Alex in to use the kitty litter and give him a tour of their apartment where he steals various things. But when Alex comes clean after seeing how friendly his hosts are, he learns that Mike and Phil are crazed sociopaths and barely escapes being tortured by them. Meanwhile, a goose named Shane (voiced by Adam Scott) explores Central Park and meets a swan named Olivia (voiced by Molly Shannon) who is led to believe that Shane is a Black Swan. His secret is found out later at a club and has to come clean.

A Papillon named Phil is taken to a dog park, which is viewed as a prison by the dogs in it. Phil is challenged to a showdown by a poodle named Angela (voiced by Chelsea Peretti). Phil and a pug named Mike plan an escape to avoid the showdown. Meanwhile, a secret is revealed among four dogs being walked; two dogs, Rusty and Princess (voiced by Kumail Nanjiani and Ellie Kemper respectively), met on a first date.

As the mayor covers up the death of a business partner who overdosed, a teenaged Phil Jr. takes credit for the pants that his friend Mike invented to impress a girl he has a crush on. Meanwhile, two moths (voiced by Duncan Trussell and Kate Berlant) talk to their friend Kevin (voiced by Pete Holmes) as he tries neon light for the first time while a fish couple (voiced by Thomas Lennon and Kerri Kenney) argue in front of another couple (voiced by Mary Holland and Tim Baltz) during dinner, causing a tense situation.

Pigeon Phil runs into trouble after being reunited with the father who abandoned him while Mike struggles to encourage his son to be a seagull scout. Meanwhile, two turtles fight over the love of a mechanical frog while a skunk learns the truth about his date's past as a sexual deviant.

Within the course of a day, a pair of flies experience the highs and lows of life in all its stages; a self-conscious horse is encouraged to let it out; bodega-dwelling cats rap.

The mayor attempts to smear the politician by planting drugs in his house. But as all hell breaks loose when the mayor learns the politician was sleeping with his wife, two squirrel brothers find their survival skills tested while on a journey to freedom after their tree was knocked down by lightning. Meanwhile, at a pet shop, a snake and her mouse prey face off while pet store puppies settle a turf war.

After being abducted as lab rats for Pesci Co., Phil Jr. and Mike begin to lose their grip on reality as they enter a love triangle with an imaginary friend. Meanwhile, two fleas ponder life while stuck on a monkey's back; an algae questions its existence.

As a virus sweeps New York, pigeon Mike's son Jacob expresses jealousy over his angelic little brother before it turns into guilt when his negligence got his brother killed. The resulting guilt trip, spurred further by his parents' grief, sends Jacob on a wacky spirit quest that teaches him about courage and responsibility; two foxes rap about their tough life on the city streets.

An old dog, Dorothy (voiced by Whoopie Goldberg) reflects on her life and doles out sage advice as her owner, the news reporter, has a final confrontation with Dr. Labcoat after he barricaded himself in Pesci Co. Meanwhile, Mike and Phil Jr. appear to be going their separate ways as their high school graduation approaches. The season ends with Dr. Labcoat wiping out the entire human populace of New York including himself with the animals taking charge.

Three years after Doctor Labcoat wiped out the entire human populace of New York City, called "Green Day", two Army personnel (Demi Moore and Mel Rodriguez) based out of New Jersey assigned two soldiers (Phil Matarese and Mike Luciano) to oversee the city that people can't go into via video feed. The animals of New York City turned it into little kingdoms: Rat Town, Ye Olde Horseburg, Squirrel Square, Dog Centre, GrabbagVille, Pigeon Heights and The Democratic People's Republic of Kitty City. The two rats, Phil Jr. and Mike, go on a Dude, Where's My Car?-like quest and encounter multiple species and terrors along the way.

In a post-owner world, dog Phil struggles to adapt, fighting to steer away from human dependency.

The heroic saga of a diminutive, but fiercely heroic bird who makes his way to Pigeon Heights, where he is tasked with saving the day.

In the new classist society that's been established among the equine community, a rich horse's daughter finds herself in a love triangle.

After a freak accident brings an assorted pile of random objects to life, the sentient items experience all of life's ups and downs before the effects wear off. Paper Mike, the only remaining animate object, uses his genius to develop a machine to enable the animals to understand each other.

The inter-species residents of GrabbagVille face drama when given the ability to communicate with one another along with the reptiles attempting to conquer them, the GrabbagVille residents rebuilding their home while reverse-engineering portable translation devices for all of New York's animals.

Following the verdict of Jim Carrey vs. Adam Sandler, Phil Jr. and Mike are forced back together on a diplomacy trip into hostile feline territory. But they learn it, and its despotic leaders, were a ruse as Phil decides to bring everyone together in a big music festival he names Roachella. Meanwhile, motivated by treason to save the animals from being blown up by the government, soldiers Phil and Mike are caught while revealed to be on a reality gameshow.

Since the "Green Day" incident, the American government set up a gameshow that roots out potential traitors with soldiers Phil and Mike having lasted for three years before they finally break with a faked message from the Labcoats. The two are then brought up to be horrifically tortured when the real Labcoats, under a brainwashed Executive 3, appear to rescue them while sabotaging the government's plans to bomb New York.

Rats Phil and Mike hold the Roachella music festival, only for chaos to ensue among the animals through a group of Jim Carrey-supporters furious at the Carrey vs. Sandler verdict and the humans' nuclear missile. The crisis is averted, but the series ends with the fully unified animals openly declaring war on the humans.