Background: Pain is a sensory modality, which in many cases represents the only symptom for the diagnosis of several diseases. It often has a protective function. Although morphine has reigned for centuries as the king of painkillers, its rule hasn’t been totally benign. There are concerns about its addictive properties and side effects, which include respiratory depression, drowsiness, decreased gastrointestinal motility, nausea and several alterations of the endocrine and autonomic nervous systems. Since Salvia officinalis (sage) is used traditionally in the treatment of painful illnesses, it became worthwhile to evaluate its antinociceptive activities in mice. Objective: The objective of the present work is to evaluate the analgesic activity of essential oil of sage leaves by the formalin test in mice. Methods: The interaction between the plant leaves and opioidergic system on formalin-induced pain were carried out. The essential oil (0.2, 0.25 and 0.3 ml/kg) was injected intraperitoneally. The control groups were administered sunflower oil as vehicles of essential oil. Also, the LD50 of the essential oil of the plant was measured. Results: The results showed that the essential oil of the plant (0.3 ml/kg) decreased both phases of pain. Also, the antinociceptive effect of essential oil (0.3 ml/kg) and morphine (0.5 ml/kg body wt.) were reversed by pretreatment with naloxone (0.5 ml/kg). The LD50 of the essential oil was found 0.5 ml/kg, i.p. Conclusion: The potent analgesic effects were blocked by naloxone, indicating that the analgesic effects are associated with the activation of opioid receptors in the central nervous system. The present data indicate that the plant has analgesic effects on mice and the plant should be considered in future therapeutic researches.