Iranian Naja oxiana (the Elapidae family) known as cobra snake inhabits in the northwestern part of Iran. This study aimed to evaluate the edematogenic potency of the crude venom with intraplantar injection into mice. Additionally, the inhibitory effects of three different drugs (i.e., promethazine, dexamethasone, and piroxicam) on paw edema were examined. Moreover, the gelatinase activity of this venom was assessed using the zymography method. Paw edema was induced by the intraplantar injection of different concentrations of the venom (0.5-5 μg dissolved in 50 μl of normal saline) into the mice (six in each group). It was estimated through the measurement of the increase in the paw thickness (%) with a digital caliper. The paws were pretreated and the rate of changes was measured after the venom injection. Pathological findings in the treated paws were evaluated with hematoxylin and eosin staining. Paw thickness reached its maximum amount within 5 min and resolved after 1 h. This venom had no gelatinase activity using the zymography method ruling out its role in edema. It caused non-hemorrhagic diffuse edema with the infiltration of inflammatory cells (i.e., leukocytes and lymphocytes) in the dermis. Intraperitoneal pretreatment with drugs significantly inhibited the venom-induced (1 μg/paw) edema; however, all the mice died unexpectedly a day after piroxicam injection. This in vitro and in vivo preliminary study demonstrated for the first time that N. oxiana venom-induced non-hemorrhagic edema in a short time. Dexamethasone (phospholipase A2 inhibitor; 1 mg/kg) and promethazine (H1 inhibitor; 5 mg/kg) decreased the venom-induced edema (p <0.001). It is suggested to carry out further studies to identify different mediators in venom-induced edema formation.