Mr. Peabody is the world's smartest being. But Peabody is also a beagle. One day, Peabody becomes lonely and decides to adopt a young boy as a pet and assistant. He adopts a young boy named Sherman. Peabody builds Sherman a time machine for his own birthday gift. After a few modifications, Peabody turns the time machine into a "should have been machine". This results in the historical figures turning totally dumb and totally contaminating the past and now Peabody and his boy must save the timeline and fix their mistakes, by creating time paradoxes.
For example, Paul Revere is unable to make his famous ride through Boston because his horse is actually a statue. In another trip Robin Hood has suffered a head injury causing him to behave abnormally—shooting bows (rather than arrows) at peasants and wanting to steal from the penniless so as to give to the well-heeled. Anachronisms also abound such as in a visit with Nero where he plays on a violin (unknown in the West until the 9th century) and Vasco Núñez de Balboa knows about Lake Erie. In another segment, Mr. Peabody and Sherman travel to Vienna, Austria in 1799 to inspire Beethoven to compose music, but when Beethoven wanders out into the street, it is full of modern-day automobiles. Also, many times historical figures are portrayed as not being too bright, such as the case with Peter Cooper and the Tom Thumb race, where in addition to having to deal with another train (the 502 from Denver) coming the other way they must overcome the obstacles of the 50% tunnel (so named because it's only half finished) and 50% bridge (so named because the plans are only half finished). Employing various strategies, Peabody, assisted by Sherman, always finds a way to fix the problems though not always in a manner true to the historical record. In the "Gallieo" episode, Sherman travels alone, due to Mr. Peabody being sick.
- In The Simpsons' fifth Halloween special ("Treehouse of Horror V"), in the Time and Punishment segment, Homer finds himself able to travel through time by means of a magic toaster and comes across Mr. Peabody and Sherman. The characters Kang and Kodos later take on Peabody's and Sherman's appearances due to Homer's meddling with the time stream
- In the Family Guy episode "The Kiss Seen Around the World", Peter and Brian travel back in time to see Christopher Columbus. The two don similar looks to Sherman and Mister Peabody; the flashback also parodies the format of the show, with the two going back in time and Brian (the dog) teaching Peter (the human).
- Peabody and Sherman are referenced in the Teen Titans episode, Every Dog Has It's Day.
- In an episode of Robot Chicken, Sherman and Peabody travel to the amish times, in which Peabody gets killed thanks to Bullwinkle's stupidity and Sherman uses the WABAC for his own personal gain.
- Mr. Peabody and Sherman appear alongside other Classic Media characters in the MetLife commercial, "Everyone". Besides Classic Media characters, Hanna-Barbera characters, the Peanuts, and Looney Tunes appear as well.
- The 1985 film Back to the Future (part one to be exact) had a character named Otis Peabody and a son named Sherman, which was tribute to the animated characters. Unlike the famed duo, this Sherman and Mr. Peabody are hostile towards Marty and his time travel