In the Japanese version of the game, there are only 6 genres of music that Miis can sing: Rock & Roll, Pop, Enka (Japanese traditional song), Opera, Heavy Metal and Rap. The International versions of the game removed the Enka genre while and adding 3 more: Ballad, Techno and Musical.

Before the game was released internationally, many international players thought that a patch in the Japanese version fixed a glitch that had unintentionally made gay marriages possible for Miis, causing fans to complain about this feature being removed, while in actuality, Nintendo was simply fixing a data transfer issue that corrupted save data and prevented people from progressing after they transferred Mii characters from the Japan-only Nintendo DS installment Tomodachi Collection. Gay marriages are able to be performed in Tomodachi Life due to the ability to create Miis that have the appearance of Miis of the opposite gender. At the time, Nintendo initially refrained from including the ability to enter same-sex relationships, explaining that the game is not to be looked at as though it is a "simulation" of real life. However, after numerous complaints, they released a statement in 2014 stating that if a third game in the series were to be produced, they would include same-sex releationships as a real feature, which eventually happened with the release of the 2026 sequel Tomodachi Life: Living the Dream.

Four songs (Pop, Idol, Rap, and Metal) that play in the Café area are the songs that Miis can learn in the Japan-only Nintendo DS installment Tomodachi Collection. In the Japanese version of the game, lyrics (taken directly from Tomodachi Collection) can be heard during each song. In the international versions of the game, the instrumentals for each song were kept, but lyrics were removed.

The shop keepers that run the various shops have different appearances depending on the regional version of the game. The Japanese version of the game features shop keepers with Kuroko stage hand masks, in the American version they have wooden block heads, in the European versions they have robot heads, and in the Korean version they are wearing a yellow racing helmet.

In the Japanese release, there is an event that can be seen at the Fountain called "Shiritori", in which a category will be chosen at the beginning of the game, such as general word association or food association. Two Miis will then come up with words which begins with the final kana of the previous word, and if either Mii repeats a word that has already been said, they will automatically lose. The North American version of the game replaces this event with one called "Rap Battle", in which two Miis try to insult each other in rhymes until one of them cannot come up with a rhyme. However, the European version not only contains the "Rap Battle" event, but also an English version of the "Shiritori" event called "Word Chain", where instead of coming up with words that begin with the final kana of the previous word, two Miis have to come up with words that begin with the letter that the previous word ended with.

In the original Japanese release, the daily donations are collected in a wooden box, whereas in the western versions they're collected in a silver piggy bank.

In the Japanese and Korean versions of the game, between 7:00 PM and 12:00 AM, a married couple can sometimes be seen taking a bath together in their bathroom, occasionally with their child. Because Western cultures consider bathing a solitary activity, this scene was removed from all other localized versions of the game. In its place is a scene where one of the homeowners' silhouettes is seen in the shower, their form obscured by being rendered as a silhouette on the door.

When a Mii gets a letter from someone asking them to go to the roof, one of the things that the Mii in disguise says is "Our Princess is in another castle.", a clear reference to Super Mario Bros.

In the Japanese version of Tomodachi Life, the Age-o-matic item worked differently, as it only temporarily turned a child Mii into an adult Mii. It is only permanent when used on child couples or mixed adult and child couples who want to marry, and the effect gets immediately cancelled when they divorce. In the International versions of the game, this was changed so that the effect becomes permanent when used. Because of this, the Kid-o-matic item was created exclusively for the international versions as a way to reverse the effects of the Age-o-matic (and allowing adult Miis to become children).

The Plane (Nintendo 3DS Image Share) and the Observation Tower were created exclusively for the International release of the game, with the Observation Tower serving the role originally used by the Mii Apartments rooftop in the Japanese release.

Nintendo of Europe made a commercial using Tomodachi Life's Concert Hall feature to celebrate the announcement of The Legend of Zelda: Majora's Mask 3D in 2014.

As Miis are able to play a Wii U, sounds from the Wii U games Nintendo Land and Game & Wario can be heard.

The description for the R.O.B. treasure in the North American version of the game lists it as an "official Smash Brawler", referencing R.O.B.'s role as a fighter in the Super Smash Bros. series starting with Super Smash Bros. Brawl.