A part of the Metroid series, it features gameplay in both first- and third-person perspectives, and is the first installment of the franchise to feature melee attacks which could only be executed when an enemy's health was reduced to a certain degree. The game gave significant focus on plot and characterization, with extensive usage of cinematics and voice acting. The regular gameplay features a third person perspective, where players hold the Wii Remote horizontally. Samus can jump, fire the arm cannon, and turn into a morph ball, which can roll into narrow passages and drop energy bombs. While gameplay is similar to early Metroid titles, the game's environments are three-dimensional and movement is not limited to a two-dimensional plane. Other M is the first in the series to feature a melee combat system. With well-timed button presses, players can use special techniques such as the Sense Move, which allows them to dodge enemy attacks, and the Overblast, where Samus jumps on the enemy and fires a charged shot at point-blank range. When the Wii Remote is pointed towards the screen, the angle switches to a first-person view, where players can lock onto targets and fire missiles; however, players cannot move in this perspective. There are several instances where players will have to constantly switch between play modes; for example, fighting off a horde of flying enemies in third person, while switching to first person to destroy their spawn points. Additionally, the first-person mode is also used in exploration, such as locating hidden items.

In the fictional chronology of the Metroid series, Other M is set between the events of Super Metroid and Metroid Fusion. The story follows bounty hunter Samus Aran, who investigates a derelict space station along with a Galactic Federation platoon, which includes her former commanding officer, Adam Malkovich.