The game takes place on a technologically advanced world centuries after Mega Man Zero 4. Humans and Reploids now coexist peacefully, both treated as humans due to the new laws.

In time, the habitants of Earth managed to revive some of the former nations. However, preventing further prosperity like the days of old, incidents around the world began where some of the machine life forms became Maverick, making some areas dangerous for the inhabitants, and soon this activity obstructed exchange between nations.

The nations became divided into areas designated as the Inner, where it was safe for humans to live, and the Outer region where the dangerous Mavericks appeared. Great developments were made due to the efforts of the corporation Slither Inc., which possesses technology unearthed from historic ruins in the outlands. Peaceful life is maintained by receiving the technology offered by Slither Inc. in the central areas of cities.

In the frontier regions where the crisis management of countries still doesn't reach, damage from attacks by Mavericks (general term for Reploids and Mechaniloids that threaten the peace) still occur. The humans in these areas developed the self-defense organization known as the Guardians. They defend the frontier regions and investigate the cause of the Maverick element.

Slither Inc. uses the technology developed from historic ruin finds essentially as a lifeline for the cities, providing goods to its people such as energy resources. It is not necessarily a bad thing that the company has more or less grasped the lifeline of the cities, at least for the people in those cities. Slither Inc.'s president is named Serpent. Serpent is considered a wonderful person who raised the company on his own by excavating the ancient technology sleeping in the Outlands. Furthermore, he has arranged a Mechaniloid army in his company, and is said to have repeatedly saved countries from Maverick attacks in the past.

On the other hand, the Guardians in the frontier regions are considered to be unassociated private ventures. They make the "Guardian Base," a gigantic flying ship, their headquarters, and they take people on a volunteer basis to not only defend the frontier areas but also investigate the Maverick source. The original leader of the Guardians disappeared during the investigation of an Outlands area, and command has been taken over by the young girl named Prair