Milhouse is not popular, but his intelligence is of a more studious nature than Bart's. He is also very gullible, thus he is constantly led into trouble by Bart, who is not shy about taking advantage of his naïve and trusting nature. Milhouse is one of the few residents in Springfield with eyebrows. He has a little Shih Tzu dog, as revealed in the episode "Lisa's Date With Density".

Milhouse is constantly being bullied in some form or another by Nelson, Jimbo Jones, Dolph and Kearney, to the point of where Bart questioned Milhouse by saying "Milhouse! I thought you had a three o' clock wedgie with Nelson." to which Milhouse casually responds "I had to reschedule." They often inflict extreme acts of physical violence upon Milhouse. They do this because they believe he is a nerd or a geek of some sort. He wears eyeglasses and cannot see without them, and when his glasses are off, his eyes appear to be small dots. In "Sideshow Bob Roberts," the schoolyard bullies wrapped Milhouse in bumper stickers and placed him in a shopping cart. After Jimbo claimed that "the mummy's ready for his mystical journey!", the bullies pushed the cart with Milhouse down a very steep hill. He is harmed frequently, and on some occasions he is injured by dangerous hazards, including being run over by a train, falling down a waterfall, being electrically shocked, having his head polished to bone, etc. In the episode "Homer Loves Flanders", Mr Burns has Milhouse crippled in order to inspire the local football team. He frequently visited a female psychiatrist called Dr. Waxler until she got fed up by his frequent callings and blocked his number so he could not bother her again. In fact, in "Bye Bye Nerdie", it is implied that Milhouse endured bullying so severe on his first day at Springfield Elementary, that he has to take pills to repress the memories.

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 portrayed 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 to his girlfriend 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. In an attempt to purposefully enrage Homer, at one point Bart stated that he once felt "a little attracted to Milhouse", sending Homer into a mindless rage. It would appear that Bart and Milhouse are the same height but in the episode "Radioactive Man" it is revealed that he is an inch taller than Bart.

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 “The Cartridge Family”, Milhouse implies that he is an excellent cook.

Milhouse is fluent in Italian due to visiting his English language-hating grandmother Sofia in Tuscany for two weeks every year. Because of his grandmother's beatings, Milhouse learned Italian and started to wet his bed. In "The Last of the Red Hat Mamas" his grandmother called him Milhouse Mussolini van Houten which hints to Milhouse's middle name, Mussolini.

Milhouse is allergic to honey, wheat, dairy, non-dairy and even his own tears. In the episode, "Little Orphan Millie", it is revealed that Milhouse is part Dutch and Danish, in the episode "The Last of the Red Hat Mamas" that he is part Italian. In another episode, it is revealed that Milhouse is part Greek when he mentions receiving a gift from his Greek grandmother for Greek Orthodox Easter. In the episode "Brawl in the Family", Milhouse told Bart he deserved a social worker because he had a stigmata which he suffered in his palms.

Milhouse harbors a hopeless crush on Bart's younger sister, Lisa, and he is usually clumsy around females. Although he and Lisa do not have a full relationship together, they are very close friends, as shown in "Lisa's Date with Density" when she admits she liked Nelson. In the end of that episode, after she has stopped liking Nelson, Milhouse asks Lisa who will be her next crush; Lisa answers that it could be anybody and Milhouse rejoices.

Milhouse's feelings for Lisa have been used in episodes set outside of the show's main storyline. For example, the episode "Lisa's Wedding" shows what the future might hold for Springfield in the year 2010. Milhouse is Homer's boss at the nuclear plant, and after learning of Lisa's impending marriage, Milhouse recalls an earlier date with Lisa where she says she may never marry, then angrily prepares Homer's annual review. Later in the episode, Lisa wonders if it's acceptable to wear a white wedding dress, suggesting that she had already lost her virginity to Milhouse; Marge, however, says "Milhouse doesn't count."

Though Lisa has always been pretty annoyed by the mere idea of going out with Milhouse, as seen in episodes like "Lisa's Date With Density" and "Future-Drama", when Milhouse starts tutoring Lisa in Italian and takes her to Little Italy, Lisa start to develop a secret crush on him, until she caught Milhouse with another girl called Angelica in the episode "The Last of the Red Hat Mamas".

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 (although a girl strongly resembling her appears in "Bart Sells His Soul", complaining to Moe about a cold "sodie"); 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 accidentally kisses Homer Simpson during a game of spin the bottle that Homer interrupted.