The most distinctive physical traits of the only child of Kirk and Luann Van Houten are his extreme nearsightedness (depicted by very small eyes), requiring thick glasses to correct, and a huge nose about the size of a softball.
Despite being considered a nerd, Milhouse is of average intelligence and has poor social skills. He is also very gullible, thus he is constantly led into trouble by the mischievous Bart, who is not shy about taking advantage of his naive and trusting friend. Milhouse is one of the few residents in Springfield with eyebrows. Homer is often heard calling him "Bart's weird friend", "that little wiener" or "the sad weird kid".
On one occasion, Bart got Milhouse placed on the FBI's Most Wanted list, even though they are friends, and he once tried to lure Milhouse into a cactus. This kind of torture is used in many episodes, where Bart tries either to get Milhouse in trouble or to hurt him for no reason, making Milhouse's and Bart's relationship even more questionable. On one occasion, Bart introduces Milhouse and attempts to explain why they are friends. He cannot come up with a real answer and admits that it is due to geographical reasons. However, Bart admits in "Little Orphan Millie" that he really loves Milhouse. Homer also seems to like joining in on his son's torment of Milhouse (constantly referring to him as "that little wiener Milhouse"). Sometimes Homer even seems to despise Milhouse and Bart's friendship. In the episode "Burns, Baby Burns" Larry, Mr. Burns' son brings Homer to eat at his house. Mr. Burns then asks Homer if his son "brings home nitwits and make you talk to them" to which Homer answers "Oh, all the time! Have you ever heard of this kid Milhouse? He's a little wiener..." before being interrupted by Burns.
The writers frequently make Milhouse the butt of a variety of jokes, ranging from being beat up by Nelson for delivering a love note from Lisa (that Nelson thought was from Milhouse himself), to having the door slammed in his face while playing Pin the Tail on the Donkey, to having his possible budding homosexuality given away by his school counselor, to making him a wanted fugitive (see above), to inadvertently inheriting Bart's dismal permanent record at school through a side deal arranged between Bart and Edna Krabappel and Principal Skinner, which will disqualify Milhouse from "all but the hottest and noisiest jobs".
In the episode, "Little Orphan Millie", it is revealed that Milhouse is part Dutch and Danish and in the episode "The Last of the Red Hat Mamas" that he is part Italian.
Milhouse's first girlfriend was Samantha Stanky, a new student who had moved to Springfield from Phoenix, Arizona in the episode "Bart's Friend Falls in Love". After her father caught her and Milhouse kissing, he sent her to a French Canadian Catholic girls' school. She hasn't been heard from since; however, she is seen in the background in some episodes. While Milhouse's official first kiss was with Samantha Stanky in the aforementioned episode, it was contradicted in the episode "The Way We Weren't", where Milhouse claims his first kiss was with Homer Simpson during a game of spin the bottle that Homer interrupted.
Milhouse is allergic to honey, wheat, dairy, non-dairy and even his own tears. He drinks Soy milk and says that real milk can kill him (though when Homer hands him rat's milk, which Milhouse believes to be cow's milk, he drinks it).
He has also demonstrated that he is a skilled Vespa rider, although he is obviously not legally entitled to operate a scooter on public roads. It is also in this episode that Milhouse had come closest to wooing Lisa, as she even kept a picture of Milhouse in her room while practicing Italian. It is implied that she is captivated by his impressive command of the language during a rather romantic outing to the local Italian immigrant establishment. However, he once again reaches a roadblock due to his ongoing fatal flaw when it comes to girls.