After countless years of conflict, Tom Cat and Jerry Mouse relocate to New York City for a fresh start. Tom, who dreams of becoming a pianist, plays in Central Park acting as a blind cat to attract people while Jerry is in search of a new home. During one of Tom's performances, Jerry picks a fight with him which ends with Tom's piano destroyed, Jerry running off and Tom clashing with a gang of alley cats led by Butch.
Kayla Forester is a young woman who does odd jobs. She ends up bumping into Tom while he is chasing Jerry which makes the cloths she is delivering very messy, eventually getting herself fired. Distraught, Kayla visits the Royal Gate Hotel and ends up with the task of helping Terrance Mendoza, an event manager, with a high profile wedding by using a fake resume. At the same time, Jerry takes up residence at the hotel where his regular shenanigans involve stealing food and items to ramp up his new lifestyle.
As the wedding couple, Preeta Mehta and her fiancé Ben, along with their pets Spike and Toots arrive at the hotel, Kayla and Terrence both greet them. Kayla charms the couple, unaware of Jerry stealing from Preeta's handbag. As the couple are escorted to their rooms, Jerry's presence is made known which puts the wedding at risk. Kayla offers to help catch Jerry without anyone knowing which impresses Henry DuBros, the owner of Royal Gate Hotel. In her pursuit to catch Jerry, Kayla befriends Cameron, a bartender, and also realizes Jerry won't be easy to catch.
Meanwhile, a depressed Tom falls into despair until he notices Jerry inside one of the hotel rooms. Filled with rage, Tom goes after him, ending up fighting and wreaking the whole room. Kayla comes to check due to noise complaints and befriends Tom because of the same goal Kayla has of catching Jerry. Kayla persuades DuBros to hire Tom and DuBros hires him, despite Terrance's disagreement.
After trapping Jerry with a few scuffles, Tom succeeds in packing him out of the hotel. Meanwhile, Kayla learns from Preeta that her engagement ring is missing and offers to help without Preeta's fiancé knowing, sparking a friendship between them. Learning that Tom has gotten rid of Jerry, Kayla celebrates with Cameron while Tom plays the piano. However, Jerry returns and drops a bowling ball on Tom which Kayla notices. Jerry reveals that he had Preeta's wedding ring with him ever since and agrees to give it back to her if Kayla lets him stay.
Before Kayla can agree, Terrence returns from walking Spike all stressed up. Jerry disappears into Kayla's coat pocket which Terrence tries to look into but ends up creating a huge scene with Spike, Tom, and Jerry messing up the hotel reception. Terrance is put on leave while Kayla takes over as event manager. However, Tom and Jerry's shenanigans almost put Kayla's job at risk until she puts aside the cat and mouse's differences and tells them that they have to get along and spend a whole day together tomorrow as far away from the hotel to which they agree, if they want to stay in the hotel.
Tom and Jerry bond during their trip while Kayla gets everything set-up for the wedding. Unfortunately, the two are taken to a pet compound when they inadvertently disrupt a baseball game. When Terrance visits Tom and Jerry, he feeds lies about the duo, separately angering both of them. At the start of the wedding, Terrance ends up enciting Tom and Jerry to fight, ultimately ruining the wedding and leading to Kayla quitting and Tom being kicked out of the hotel.
Knowing that it is their fault the wedding was ruined, Tom and Jerry finally put aside their differences and decide to try and fix everything. After they convince Kayla, everyone, along with Terrence who reconciles with Kayla, make a plan. Tom and Jerry pursue Preeta on an electric skateboard and led her to Ben. The end result is that the wedding ends up better than planned, at the park. Preeta and Ben open up with each other while Kayla, along with the girl who she stole the resume from, gets the job at the hotel.
As the film ends, the wedding continues as planned until a mishap caused by Jerry reignites his longtime battle with Tom, causing the cat and mouse to return back to their old habits of antagonizing each other.
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