Players control the bounty hunter Samus Aran, who investigates a space station infected with shapeshifting parasites known as X.

Fusion was acclaimed for its gameplay, controls, graphics and music, though its shorter length and greater linearity received some criticism.

Like previous games in the series, Fusion is set in a large open-ended world with elevators that connect regions, which each in turn contains rooms separated by doors.

[3] The gameplay involves solving puzzles to uncover secrets, platform jumping, shooting enemies, and searching for power-ups that allow Samus to reach new areas.

Power-ups are obtained by downloading them in Data Rooms or absorbing a Core-X, which appears after defeating a boss.

[9] Bounty hunter Samus Aran explores the surface of the planet SR388 with a survey crew from Biologic Space Laboratories (BSL).

The BSL ship she was escorting recovers her body and transfers it to the Galactic Federation for medical treatment, who discover that the X has infected Samus' central nervous system.

[12]: 88  The vaccine gives her the ability to absorb the X nuclei for nourishment,[4]: 8  but burdens her with the Metroids' vulnerability to cold.

[18] Samus avoids the SA-X and explores the space station,[12]: 98, 107  defeating larger creatures infected by the X to recover her abilities.

[12]: 135–136  The computer berates Samus for ignoring orders and admits that the Federation was secretly using the lab to breed Metroids.

[20] On her way to her ship, the computer orders Samus to leave the rest of the investigation to the Federation, which plans to capture SA-X for military purposes.

[21] Knowing that the X would only infect the arriving Federation troops and absorb their spacefaring knowledge to conquer the universe, Samus states her intention to destroy the station.

[25] En route to initiate the propulsion sequence, an SA-X confronts Samus, who defeats it and sets the BSL station on a collision course with SR388.

[28] The footage showed Samus in a dark suit, running on walls and ceilings, with simpler, more "Game Boy Color-like" graphics.

[31] Fusion's gameplay, screen layout, and controls mimic those of Super Metroid, with enhancements.

[32] Sakamoto decided to create an original story instead of remaking a Metroid game because he wanted to do "something really unprecedented", and looked forward to the response.

[33] Fusion introduces gameplay mechanics such as a more direct, almost mission-based structure that supports the player to explore areas.

The health and missile drops are replaced by X Parasites that are similarly released after defeating enemies.

[54] GamesRadar and GamePro felt that Fusion was too short, but "love[d] every minute of it", finding the hidden secrets and new power-ups "sublimely ingenious".

[5] Scott Pelland Nintendo Power heralded it as a return to the classic Metroid action gameplay.

[47] Fusion did not feel new to GameSpy, which complained that even the final enemy encounter draws heavy inspiration from Super Metroid.