In Mouse Guard, mice struggle to live safely and prosper among all of the worlds harsh conditions and predators. Thus the Mouse Guard was formed. They are not simply soldiers that fight off intruders; rather, they are guides for common mice looking to journey without confrontation from one hidden mouse village to another. The Guard patrol borders, find safeways and paths through dangerous territories and treacherous terrain, watch weather patterns, and keep the mouse territories free of predatory infestation. They do so with fearless dedication so that they might not just exist, but truly live. In this first issue of Mouse Guard, Saxon, Kenzie, and Lieam are dispatched to find a missing merchant mouse that never arrived at his destination. In doing so they stumble onto much more than they had bargained for.

Hiding within the ranks of the mysterious militia known only as 'the Axe', Lieam is unaware that his Guard companions, Kenzie and Saxon, have been left for dead outside Barkstone's gates. Celanawe, a hermit and stranger of the mouse cities, retrieves and drags them to his secluded home. The hermit Celanawe proclaims himself to be none other than the Black Axe, famed champion of the Mouse Guard who has been long presumed dead. Saxon, escaping his bonds, engages in combat with Celanawe, which results in the hermit's house burning down, but not before Kenzie is able to convince Celanawe that they must work together to stop the Axe. The Black Axe's legendary axe has been pilfered, which the two Guard mice agree to help recover. Elsewhere, Lieam is uncovered by the Axe as a spy and he realizes that the Axe's leader has a familiar voice.

The mice Saxon and Kenzie find a new ally in a mouse named Celenawe, who claims to be the ancient hero of the mice, the Black Axe. Together they track the treacherous Axe army in the hope of retrieving his missing axe.