In the lively streets of New York City, 12-year-old Emily Elizabeth Howard (Darby Camp) faces the tumultuous trials of middle school, her spirit frequently dampened by the sharp remarks and sneering mockery of her nemesis, Florence. The only ray of sunshine in her challenging world is her steadfast friend, Owen Yu (Izaac Wang), who serves as a guiding light amid the shadows of adolescent hardships. However, just as it seems like a brighter future is in store, Emily’s mother, Maggie (Sienna Guillory), leaves for a business trip in Chicago, placing Emily under the care of her unconventional uncle, Casey (Jack Whitehall).
During a fortuitous encounter with Mr. Bridwell (John Cleese), a compassionate animal rescuer, Emily's life changes dramatically when she is introduced to an endearing little red puppy, abandoned by dogcatchers. Bridwell shares that this unique pup will flourish in proportion to the love it receives, presenting Emily with a chance for happiness. Despite Casey's pragmatic concerns regarding their apartment's strict no-pets policy, Emily's heart is swayed, and she names the puppy Clifford. While initially hesitant, Casey ultimately agrees to let her keep Clifford for just one night—a decision that cascades into a whirlwind of transformations. The following morning, however, brings shocking news as Clifford has inexplicably ballooned in size, his mighty paws thumping against the floor in a joyful yet overwhelming manner.
As Emily and Casey scramble to conceal their enormous new friend from the well-intentioned but intrusive Mr. Packard (David Alan Grier), their attempts to manage Clifford take them to a veterinarian, though an unexpected chain of chaotic events unfolds when Clifford wreaks havoc in the office. News of the giant dog goes viral, thrusting Emily into a whirlwind of both excitement and turmoil. Determined to uncover more about Mr. Bridwell’s past accomplishments with animals, Emily finds herself in a series of chance encounters with Clifford, even orchestrating a memorable moment where Clifford playfully embarrasses Florence, marking an uplifting milestone in her social journey.
Meanwhile, Zac Tieran (Tony Hale), the ambitious head of Lyfegro, a leading biotech company, becomes fascinated with Clifford upon receiving a photo from his diligent assistant Colette (Jessica Keenan Wynn). Seizing the opportunity, he devises a cunning plan, falsely claiming credit for Clifford's remarkable growth, and sets out on a mission to find the pup. Amid this intrigue, Emily and Casey find themselves facing eviction at the hands of Packard, who has been alerted by Tieran. Their fight for Clifford escalates as they evade both law enforcement and Tieran’s intimidating henchmen while seeking refuge in Owen's van alongside their brave neighbors.
As night falls, they find sanctuary in Owen's stylish apartment, where Casey proposes a daring mission: track down Mr. Bridwell to reverse-engineer Clifford’s unexpected size, or risk losing him to an animal sanctuary in Shanghai where Mr. Yu (Russell Wong) operates. In a desperate bid for help, they turn to Yu, but their hopes are dashed when they learn Bridwell has passed away. With no other options, they concoct a plan to smuggle Clifford to safety, only to have their efforts foiled when Tieran’s men intercept their escape.
In a tumultuous climax, Emily uncovers that the real Bridwell might still be alive when she faces off against Tieran at the Manhattan Bridge Park. With emotions running high, she pleads for support, realizing that Clifford's extraordinary growth is a direct reflection of her love for him. The sound of her heartfelt words anchors the crowd, and just as things seem to reach a pivotal moment, Tieran's arrogance counters her plea with a revelation about an ID chip that proves Emily's rightful ownership of Clifford. This revelation ignites a series of developments, culminating in Tieran being held accountable for his devious schemes.
As the dust settles, Emily is reunited with her mother, Maggie, and Packard courageously reinstates their own stability by nullifying the eviction notice. With Clifford now an integral part of their family dynamic, Casey seizes the opportunity to create engaging stories highlighting Clifford’s adventures, marking a significant turn in his career. The community comes together to construct a massive doghouse for Clifford, symbolizing not just the physical space he now occupies, but also the heartwarming power of love, friendship, and resilience in overcoming challenges.
