Mrs. Brisby, a timid and introverted mouse widow, finds her family's safety in jeopardy due to an unseasonably warm spell that compels Farmer Fitzgibbons to begin plowing his fields ahead of schedule. This rush threatens the fragile cinder block that she and her four children—Martin, Theresa, Cynthia, and young Timmy—call home. While a typical move to a safer location would be their usual course of action, Timmy's serious illness from pneumonia complicates matters, keeping them rooted in their perilous situation.
In a moment of desperation, Mrs. Brisby seeks guidance from her wise neighbor, Auntie Shrew, who urges her to muster courage for the sake of her family and suggests she meet the enigmatic Great Owl. Despite her trepidation—after all, owls are natural predators to mice—Mrs. Brisby, with the help of a clumsy yet earnest crow named Jeremy, embarks on a daring journey to seek the owl's counsel. Upon learning of her late husband, Jonathan Brisby, the owl shares a critical piece of advice: seek the help of the secretive Rats of NIMH, who reside within the rosebush next to the farmer's house.
Upon reaching the rats, Mrs. Brisby discovers a complex society that draws upon electricity stolen from Fitzgibbons. She encounters Dr. Ages, her family’s doctor, who, astonished by her encounter with the Great Owl, acknowledges her formidable challenge. The rats' leader, Nicodemus, reveals their history as lab animals transformed into intelligent beings after escaping the clutches of NIMH, and pledges to assist her, forever indebted to Jonathan for his past heroism.
However, lurking beneath this newfound alliance is Jenner, a power-hungry rat with nefarious intentions to usurp Nicodemus and sabotage their plans for a brighter future in Thorn Valley. As Mrs. Brisby courageously offers to deploy a plan to sedate Fitzgibbons' ferocious cat, Dragon, circumstances turn dire when she becomes trapped and overhears a plot that puts her children in peril.
As the rats prepare to execute their daring operation, tensions reach a boiling point when Jenner's treachery unfolds, leading to a tragic confrontation that leaves Nicodemus dead. Driven by a mother’s instinct to protect her children, Mrs. Brisby draws upon the amulet bestowed to her by Nicodemus to harness courage and empower herself. With unwavering determination, she manages to lift her home from impending doom at the last moment.
The dawn following these harrowing events brings renewed hope, as Timmy begins to recover and the now-abandoned rosebush gets scrutinized by NIMH. Jeremy returns, triumphant with strings to weave his future, only to find the Brisby home magically relocated and unsuspectingly adorned by nature, while love is unexpectedly waiting to unfold. As Mrs. Brisby's children tend to her burned hands from the amulet’s power, a harmonious turn of events blossoms, as relationships begin anew with the arrival of Jeremy’s serendipitous companion.
