In Victorian London, a clever unseen criminal begins orchestrating a perfect plan on paper, starting with a daring robbery that involves three cunning cats stealing a valuable pink diamond. The pursuit begins when three constables spot them, but the cats swiftly escape onto the rooftops, gliding effortlessly into the night sky, giving the stolen gem to a mysterious horseman. Early next morning, Dr. Watson rushes to 221B Baker Street to inform Sherlock Holmes about the theft. Holmes immediately calls upon his resourceful pet mouse, Jerry, to bring him the latest newspaper, which he uses to gather clues about the crime.
While Jerry heads out to purchase the Times, he encounters Tom, and they exchange information with Holmes. Once Jerry returns with the paper, Holmes, Watson, and Tom examine the clues, which lead them to the Bruce Nigel Theatre, where they spot a performer named Red, voiced by Grey DeLisle. Holmes quickly deduces that Red is being blackmailed and suspects that the mastermind behind the scheme is Professor Moriarty, voiced by Malcolm McDowell. Holmes predicts that a famous diamond called the Star of Punjab, extremely sensitive to light, is their next target, especially since an upcoming solar eclipse is scheduled for the following day.
The next scene unfolds at the Punjab Embassy, where Spike and Tyke, voiced respectively by Phil LaMarr and Greg Ellis, are tasked with guarding the invaluable Star of Punjab diamond. Spike tries to teach Tyke how to be a vigilant guard dog, but chaos ensues when the three cats from the previous night sneak past and manage to steal the diamond, leaving behind only a small button as evidence of their escape. They slip through a tunnel leading from Red’s house, which the cats use to vanish just before Holmes, Tom, and Jerry arrive to investigate.
Holmes, Watson, and Jerry embark on a mission to track down the shop where the button originated. Meanwhile, Red, along with Tom and Tuffy, voiced by Kath Soucie, heads to Holmes’ flat. Police suspicion falls on Red, and a duo of cartoonish detectives—Butch and Droopy, voiced by Jeff Bergman and Jeff Bergman respectively—race to stake their claim on the case. During their chaotic chase, Tom accidentally drops a lantern on Butch’s head, leading to a wild pursuit resulting in entrances and escapes from iconic London landmarks, including St. Paul’s Cathedral.
Inside the cathedral, Tom, Jerry, and Tuffy hide in the organ, while Droopy and Butch attempt to find them. The chase culminates at a graveyard, where the trio uncovers the Star of Punjab hidden in the cemetery. Just as they reach the scene, the shadowy horseman appears once again, but Jerry secretly snags a key from him. Red, seeking safety, visits her friend, a professor, only to be accidentally knocked out and locked outside with Tom, Jerry, and Tuffy. They hide in a stable, where they find and inspect a strange machine owned by the villainous Moriarty.
The professor reveals himself as Moriarty, outlining his sinister plan to use the eclipse’s light to turn the diamonds into a deadly heat ray. This weapon, fueled by the Star of Punjab, is designed to be ricocheted off mirrors strategically placed around London's landmarks, aiming to slice a hole through the Tower of London and steal the Crown Jewels.
As Moriarty heads towards the Tower with Red kidnapped, Spike and Tyke are left to guard the jewels but are tragically caught in the trap laid by Moriarty’s heat ray. The cat thievery continues, and Moriarty escapes after stealing the jewels. Tom, with quick thinking, manages to stop the destructive ray just in time, and the remaining heroes rescue Red. Holmes and Watson then pursue Moriarty’s carriage as he tries to escape, leading to a dramatic fight atop the carriage, which eventually goes off the unfinished Tower Bridge.
Believed to be dead by Holmes and Watson, Red, Tom, Jerry, and Tuffy reunite at the bridge, where they ultimately save Holmes who is clinging to the edge of the collapsing carriage with the stolen jewels. Moriarty and his feline accomplices are apprehended, and the Crown Jewels are recovered. Interestingly, Droopy secures the reward instead of the duo Butch and Droopy, after chaining up Butch without him noticing.
Back at St. Paul’s Cathedral, Red marries a wolf, and they start howling — a comical ending to their adventure. As Holmes and Watson watch the scene, Jerry secretly sets Tom’s tail on fire, sparking a classic chase. The story closes with Droopy revealed as the mastermind behind the wedding, sharing an innocent smile as the scene fades out.
Throughout this lively, humorous tale, the characters engage in clever detective work, daring chases, and spectacular escapes, all set against the richly detailed backdrop of Victorian London. The film combines adventure, mystery, and comedy, showcasing the iconic characters in their greatest escapades.