Mr. Peabody is a talking dog who is the smartest being in the world in New York City. As a puppy, he was rejected by every potential owner, leading him to devote his life to science, athletics, and technological discoveries. One day, Peabody finds an orphaned infant and legally adopts him under the name of Sherman. He tutors Sherman through a series of adventures throughout history with the use of the WABAC, a time machine and his greatest invention.
After narrowly escaping the French Revolution, Sherman starts his first day of school and falls into conflict with classmate Penny Peterson, who he innocently showed up in history class with his first hand knowledge of George Washington. Penny bullies and humiliates Sherman, insulting calling him a "dog" for being raised by one, which provokes Sherman into biting her. Peabody visits Principal Purdy about the matter, but is confronted by Ms. Grunion, a bigoted child and family services agent who threatens to reclaim Sherman if an upcoming home inspection is deemed unfit for him.
Peabody invites the Petersons over for a dinner party to mend fences between the children. While Peabody charms Paul and Patty, Sherman is left with Penny. Sherman reveals the WABAC to Penny after she calls him a liar about his first hand knowledge and they joyride in it, despite Peabody's warnings.
Moments later, Sherman seeks Peabody's help to retrieve Penny, who refused to leave her engagement with King Tutankhamun in Ancient Egypt. Penny learns that she will be killed upon Tut's early death and is dragged to the wedding while Peabody and Sherman are trapped in a tomb. They escape and impersonate the god Anubis to call off the wedding. Their cover is blown at the last second, but they escape in the WABAC along with Penny.
With the WABAC low on energy, the three stop in Renaissance Florence to seek the aid of Leonardo da Vinci. While Peabody and Leonardo build a contraption to recharge the WABAC, Penny convinces Sherman to explore Leonardo's workshop with her and they bond by using Leonardo's flying machine without permission. They crash-land and Leonardo is thrilled that the machine worked but Peabody is angered by Sherman's disobedience. Returning to the present, Penny reveals Ms. Grunion's intention of reclaiming Sherman. An argument ensues between Peabody and Sherman while the WABAC draws near a black hole.
They escape but crash-land in the Trojan War in Troy, where an upset Sherman runs away to join King Agamemnon's army. When Peabody and Penny come to retrieve him, they find themselves in the battle and Penny becomes trapped in the Trojan horse as it races toward to cliff. In a rescue attempt, Sherman and Penny are saved, but Peabody appears to have gone down with the horse and is presumed dead.
Desperate to save Peabody, Sherman and Penny return to the present minutes before Sherman returned the first time to get Peabody to remedy the situation. However, the present copies of Peabody and Sherman show up, along with Ms. Grunion. Grunion attempts to reclaim both Shermans, which causes them, along with the copies of Peabody to merge and disrupt the space-time continuum. Grunion makes another attempt at reclaiming Sherman, hurting him in the process, which causes an enraged Peabody to revert to his natural instinct and bite her. As Grunion informs police, Peabody, Sherman and Penny flee to the WABAC, but are unable to travel back in time as several historic figures and monuments rain down into the present.
The WABAC eventually crashes and Peabody is apprehended by Animal Control, who plan on euthanizing him for assaulting Grunion. Sherman protests by explaining that everything that happened is his fault and declares that he would rather be a dog as good as Peabody than a person. Moved by his speech, every historical figure concurs, including the Petersons. George Washington, Abraham Lincoln and Bill Clinton support Peabody's legal custody of Sherman and award him a presidential pardon. When a vortex in the space-time continuum rips open, Sherman pilots the WABAC while Peabody handles the computations intending to travel to the future by a few minutes and undo the damage with success.
The historical figures and monuments return to their respective times, with a smitten Agamemnon dragging Grunion with him, the latter swearing vengeance on Peabody. Although it appears Peabody and Sherman are lost, they return spontaneously as The Petersons look on and celebrate. Sherman, closer to Peabody than ever, returns to school where he has become a good friend with Penny. Meanwhile, time periods are contaminated with modern traits and Grunion marries Agamemnon.
- Main article: List of Mr. Peabody & Sherman characters
- Main article: List of Mr. Peabody & Sherman historical figures
- Ty Burrell as Mr. Peabody
- Max Charles as Sherman Jones
- Ariel Winter as Penny Peterson
- Stephen Colbert as Paul Peterson
- Leslie Mann as Patty Peterson
- Dennis Haysbert as Chairman
- Stephen Tobolowsky as Principal Purdy
- Patrice A. Musick as Teacher
- Allison Janney as Ms. Grunion
- Karan Brar as Mason
- Joshua Rush as Carl
- Leila Birch as WABAC
- Lauri Fraser as Marie Antoinette
- Guillaume Aretos as Maximilien Robespierre
- Zach Callison as Pharaoh Tutankhamun of Egypt
- Steve Valentine as Pharaoh Ay of Egypt
- Stanley Tucci as Leonardo da Vinci
- Lake Bell as Mona Lisa
- Mel Brooks as Albert Einstein/Sigmund Freud
- Jess Harnell as George Washington/Abraham Lincoln/Isaac Newton/Bill Clinton/New York City Cop
- Danny DeVito as Benjamin Franklin