Kate DiCamillo´s Flora and Ulysses tells the story of the ten-year old Flora, self-proclaimed cynic and comic fan, who becomes best friends with a superhero squirrel and together, they fight against their arch nemesis.
Flora, whose parents are divorced, lives with her mother, Phyllis Buckman, in a suburban neighborhood. One day, while reading one of her favorite comics “The Illuminated Adventures of the Amazing Incandesto!”, she gets distracted by a noise. The noise is coming from the backyard of her neighbor Tootie Tickham, who accidently sucked up a squirrel with her new vacuum cleaner, “Ulysses 2000X”. Flora runs down into the backyard and rescues the Squirrel. After Flora saves its life, the always hungry squirrel gets up and surprisingly shakes the vacuum, to get some crackers. Tootie cannot believe her eyes, but well- read Flora immediately knows what has just happened. As in her favorite comic, the accident has resulted in the squirrel being given supernatural powers. Flora names the newly made superhero after the vacuum and takes the poor squirrel secretly home.
At night Ulysses wakes up and goes downstairs to find some food. There he spots the typewriter of Flora´s mom, who is a romance novelist, and this awakens his desire and a new superpower to write poetry. In the morning Flora´s mother discovers a sheet of paper in her typewriter and Flora gets in trouble for using it. But all of a sudden Ulysses appears. Flora´s mother freaks out and tells Flora that the squirrel has to go. Tootie and her temporarily blind nephew, William Spiver, come forward to release the squirrel into the wild. But instead of releasing it, the three of them go over to Tootie´s house. Because of the sheet in the typewriter, they want to find out there if Ulysses is able to type letters. And it happens: Ulysses types his first poem. But the magical moment is disturbed by Flora´s mom, calling her to come home.
There Flora´s father, George Buckman, is already waiting for her. While Flora is getting dressed, she listens to a conversation between her parents. Phyllis tells George to kill the Squirrel and bury it in a sack. Flora cannot believe that her own mother is the arch nemesis (every superhero has one and Ulysses is a superhero). In the car Flora confronts her dad with the evil plan of her mother. But Flora´s father, like always, evades the questions and offers Flora to take breakfast in a restaurant. Because Flora doesn’t want to leave Ulysses in the car, she takes the Squirrel, in a shoebox, into the donut shop. There the next incident happens: Rita, the waitress, wants to see what Flora is hiding in the shoebox. She discovers Ulysses and starts screaming. Ulysses jumps out of the box fearfully. He flies against the window and gets injured. Caring Flora takes Ulysses and together with her dad they make their getaway from the restaurant.
At Blixen Arms, the building where Flora´s dad lives, Flora notices a door sign with the name of a doctor on it. Flora thinks that the doctor could help Ulysses and knocks at the door. A delightful old lady, Dr. Meescham, opens the door. However, to Flora´s disappointment, Dr. Meescham is a doctor of philosophy. Nevertheless, thanks to her great wisdom, she is able to help Ulysses and cares for him and Flora by making them sandwiches. By the time Flora´s dad arrives, Ulysses has recovered and they want to head back home. But suddenly Mr. Klaus, the cat of the apartment owner, shows up and attacks George Buckman. Ulysses immediately knows what to do and vanquishes the nemesis.
Back at home Flora has an uneasy feeling. Nevertheless, she and her superhero friend have to fight their arch nemesis, her mother. As they walk into the house, they come across Flora´s mother and William Spiver, who are working on a new romance novel in the kitchen. Flora confronts her mother with her failed evil plan. Phyllis is furious that Ulysses is still alive, but after a conversation with George, she acts strangely and allows Flora to keep Ulysses.
At night Ulysses feels the urge to write poetry. He goes downstairs to write a poem for Flora. Suddenly Phyllis appears in the kitchen. She forces Ulysses to write a farewell letter and kidnaps him. Her plan is to go into the forest and do, what George has not been able to do and what is best for Flora: kill the squirrel.
In the meantime, Flora has woken up and realized that Ulysses is gone. She finds the letter in the typewriter and knows what is actually happening. She picks up William and Tootie and together they try to find Ulysses. While they are searching for him, Ulysses can manage to escape and, by a fortunate coincidence, ends up at Dr. Meescham´s apartment.
Flora, herself, feels a strong desire to see her dad. So they go to the Blixen Arms. There they hear loud laughter from Dr. Meescham´s flat. It is her dad´s laugh. They knock at Dr. Meescham´s door. And, surprisingly, they not only meet Flora´s dad, but also Ulysses.
Flora and Ulysses are back together. Both are very happy and everybody wants to know what has happened to him. But all of a sudden they hear a loud noise from down the hallway. It is Flora´s mother, who has been attacked by Mr. Klaus, the cat, while she was looking for Flora. They run into the hallway and want to rescue her. But the most important thing in this situation for Phyllis is that Flora is with her dad and safe.
Flora´s mother apologizes to her. Furthermore, she reads out the poem that Ulysses has written for Flora. And this poem is, of course, just the beginning of a great friendship and a lot of other adventures.