1. Bruxism and/or clenching, resulting in fatigue or dysfunction of masseter muscles (MM), may cause temporomandibular disorders. Functional support of the microcirculation is critical for prolonged muscle activity. Histamine is a regulator of the microcirculation and is supplied by release from its stores and/or by de novo production via the induction of histidine decarboxylase (HDC). IL‐1, a cytokine involved in temporomandibular disorders, is an inducer of HDC. We examined the roles of histamine, HDC, and IL‐1 in MM activity. 2. Experiments were conducted using our R+G+ model. A mouse restrained (R+) inside a narrow cylinder (front end blocked with a thin plastic strip) gnaws away (G+) the strip to escape, and the strip's weight‐reduction serves as an index of MM activity. 3. Fexofenadine (peripherally acting histamine H1‐receptor antagonist) reduced MM activity in normal mice. H1‐receptor‐deficient mice and HDC‐deficient mice displayed low MM activity. Prolonged R+G+ induced HDC activity in MM. Mast cell‐deficient mice exhibited strikingly low HDC induction in MM (and also in quadriceps femoris muscle) in response to muscle activity or IL‐1β. Mast cells were present around blood vessels and nerves in the epimysium and perimysium of MM. 4. These results, together with others reported previously, suggest that (i) peripheral histamine supports strenuous MM activity, (ii) strenuous MM activity stimulates mast cells to release histamine and to induce HDC (which replenishes their histamine pool, possibly through mediation by IL‐1), and (iii) peripheral histamine H1‐receptor antagonists may be effective at treating temporomandibular disorders or preventing prolonged clenching and/or bruxism. This article is protected by copyright. All rights reserved.