Kate is the true love interest of Griffin Keyes who they know each other for 5 years after Griffin got heartbroken by Stephanie.
Five years later, Griffin is shown to be the lead zookeeper at the Franklin Park Zoo who cares deeply for the zoo animals. That night, Griffin holds a party at the zoo for his brother Dave (Nat Faxon) who is getting married, but freaks out when he discovers that Stephanie was invited.
Dave offers Griffin to come and work with him at a car dealership, explaining that it is the best way to get Stephanie back. Griffin contemplates quitting his job at the zoo and joining his brother at the dealership.
Later, the animals hold a meeting saying that they think Griffin is the best zookeeper at the zoo and don't want him to leave, so they decide to find some way to help him win Stephanie's heart.
Jerome the Bear (Jon Favreau) suggests that they teach Griffin their animal mating techniques, but Joe the Lion (Sylvester Stallone) protests, reminding them that it's against the animal code to talk to humans.
Donald the Monkey (Adam Sandler) says that Stephanie will be at the zoo tomorrow, and all the animals have to do is make Griffin look like a hero in front of her.
The next day, Donald unlocks the door to the lion enclosure and lets Joe out, who confronts Stephanie and Dave's fiancee Robin (Steffiana de la Cruz). Kate (Rosario Dawson), the zoo's vet, manages to get them away from Joe, but Griffin fails to jump into the lion enclosure, ruining the animals' plan.
Griffin discovers that Stephanie is dating her other ex-boyfriend, a bullying alpha-male named Gale (Joe Rogan).
Joe's mate Janet (Cher) tells Griffin that the best way to attract a female is to be seen with another female, so Griffin asks Kate to go with him to Dave and Robin's wedding. Griffin then takes Bernie to T.G.I. Friday's and they bond, with Bernie telling Griffin that he's his best friend.
Griffin and Kate go to the wedding and seem to have fun together. Griffin becomes brave enough to stand up to Gale and this grabs Stephanie's attention.
After Kate tells Griffin she had a great time with him, Stephanie asks Griffin out to dinner.
Griffin accepts and they go to dinner and then go to a fashion show. Stephanie tells Griffin that his job at the zoo is holding him back, so Griffin decides to quit his job and accepts Dave's offer which upsets Kate.
Bernie also becomes upset and tells Griffin that he thought he could trust someone again, but was proved wrong when Griffin quit his job. Kate decides to leave the zoo and accepts a job in Nairobi.
Griffin becomes the best employee at the car dealership, but misses working at the zoo. Stephanie proposes to Griffin, but Griffin refuses and dumps her.
He then goes back to the zoo and apologizes to Bernie, who accepts Griffin's friendship. The animals then tell Griffin that Kate is heading to the airport.
Griffin heads out to stop her, though he does make a stop first to beat up Shane.
Then, with Bernie's help, Griffin manages to catch up with Kate on the bridge and confesses his love for her.
Six months later, Griffin and Kate are back working at the zoo and Bernie is now living in a new enclosure where he gets a great view of the city.