[3] The game includes four game modes: "Operation L", where the capsules used are conjoined into an L-shape at move at a slower pace;[7] "Virus Buster", a mode that is also in Dr. Mario Online Rx, which is played by holding the Wii U GamePad vertically and using the touchscreen to drag and drop the capsules;[7] "Retro Remedy", which uses traditional Dr. Mario series rules and lacks the gimmicks of Operation L;[3] and local and online multiplayer.

[8][9] Most of the contents are reused gameplay from old games, such as Virus Buster, which retains a similar concept from Online Rx, with the addition of updated graphics and sound.

[14] In the first week of release in Europe, Dr. Luigi was the number one bestseller on the Wii U eShop, ahead of F1 Race Stars and the re-release of The Legend of the Mystical Ninja.

[2][4] GameSpot's Heidi Kemps called Operation L "a disappointment" due to the shape's oversized nature that didn't allow for specific placement.

[8] Contrarily, IGN reviewer Scott Thompson originally thought that L-shaped pills would be a "shallow gimmick", but found it to be more entertaining than the traditional Dr. Mario gameplay.

[6] Writing for 4Players, Jens Bischoff called Operation L "practically the only unique selling point of the download" and that it wasn't enough to justify its US$15 price.

[2] Virus Buster was a favorite of Polygon reviewer Ben Kuchera, lauded for being "a more direct, intuitive way to control the game" with a steady increase in difficulty.

[8] Lee Meyer of Nintendo Life praised the online modes for utilizing handicaps to level the playing field, and because lag was "non-existent" with minimal downtime between rounds.

[5] The original Dr. Mario was released in 1990 after the success of Tetris, and, according to Schilling, the gameplay has not held up to modern standards due to its lack of change.

[6] Jeremy Parrish of USgamer shared similar opinions but said it had more replay value in comparison to prior games, mainly due to the number of modes available.