Endomorphin‐2 demonstrates potent antinociceptive effects in various pain models. The objectives of the present study were to explore the role of endomorphin‐2 in the modulation of orofacial pain induced by orthodontic tooth movement in rats. An orthodontic pain model was established in male Sprague‐Dawley rats by ligating coiled springs to mimic orthodontic force (40 g). On days 0, 1, 3, 5, 7, and 14 following orthodontic tooth movement, bite force was recorded as a surrogate measure of orthodontic pain. Ipsilateral trigeminal ganglia, trigeminal nucleus caudalis, and periodontal tissues were harvested for immunostaining. Endomorphin‐2, endomorphin‐2 + naloxone (a non‐selective opioid receptor antagonist), naloxone, and saline were injected into trigeminal ganglia and periodontal tissues to explore the role of endomorphin‐2 on orthodontic pain. The results showed that following orthodontic tooth movement, endomorphin‐2 expression levels in trigeminal ganglia were elevated on days 1, 3, 5, and 7. Orthodontic pain levels were increased on days 1, 3, and 5. The administration of endomorphin‐2 into both trigeminal ganglia and periodontal tissues alleviated orthodontic pain. Moreover, the effects of endomorphin‐2 could be blocked by naloxone completely in trigeminal ganglia but only partially in periodontal tissues. Therefore, endomorphin‐2 plays an important role in the modulation of orthodontic pain both centrally and peripherally, probably through different pathways.