The episode title is a play on "Mother's Little Helper", a song by The Rolling Stones, which in turn is a euphemism for certain prescription drugs believed to be commonly used (or abused) by middle-class women in the US and UK in the 1960s (such as barbiturate sleeping pills, amphetamine diet pills, and benzodiazepine tranquilizers).
Homer says that Bart "has gone from Goofus to Gallant", a reference to the comic strip "Goofus and Gallant", which appeared in 'Highlights', a magazine for children. Typically, Goofus would do something rude or destructive, while Gallant served as an example of proper behavior.
The Terminal Man (1974) is considered an influence behind this episode. In the film, George Segal stars as a epileptic man whom is implanted with a experimental microchip in his brain that control him when he suffers violent seizures which he soon goes out of control and becomes addicted to the electrical impulses which turns him into a violent man. In "Brother's Little Helper", Bart takes an untested new behavioral medicine called Focusyn to improve his behavior when he is diagnosed with ADHD. But, Bart soon begins suffering from drug psychosis and paranoia and refuses to go off the Focusyn which he flees and embarks on a swath of destruction.
A scene in the episode shows Marge standing in front of the tank Bart has stolen. The scene is a reference to Tank Man, the anonymous man who stood in the way of a column of tanks the morning after the Chinese military forcibly removed pro-democracy protesters from Beijing's Tiananmen Square.
At the very end Bart sings about his drugs using the Popeye theme tune. Nancy Cartwright who voices Bart, was also the voice of Woody on Popeye and Son (1987).