Abstract: Objective To investigate the effect of blocking endothelin receptors on the pain of oral cancer in rats. Methods A total of 48 Wistar rats were selected and divided into four groups: a sham group, a tumor model + normal saline group, a tumor model + trigeminal ganglion injection group, and a tumor model + tongue injection group. Before modeling, basic oral and facial mechanical pain thresholds in the four groups were measured. Walker 256 tumor cells were injected into the right tongue of rats to establish the model, and weight changes were daily monitored. On day 8 after modeling, the oral and facial mechanical pain threshold was measured, and the duration of spontaneous facial pain within 10 min was observed. On day 9 after modeling, bosentan, an endothelin receptor antagonist, was injected. Then, 1 h after injection, the mechanical pain threshold in the oral and facial region of rats was measured and 90 min after injection, the duration of spontaneous pain behavior in the facial region of rats within 10 min was observed. Results The oral cancer model of rats was successfully established by injecting Walker 256 tumor cells. The weight of tumor bearing rats significantly decreased (P<0.01), the oral and facial mechanical pain threshold of the oral cancer rats dramatically decreased (P<0.01), and the duration of spontaneous pain behavior in the facial region within 10 min substantially increased (P<0.05). Then, 1 h after injection of bosentan into the trigeminal ganglion/tongue, the oral and facial mechanical pain threshold of the oral cancer rats significantly increased (P<0.01) and 90 min after injection, the duration of spontaneous facial pain behavior within 10 min significantly decreased (P<0.01). Conclusions Injection of bosentan can block endothelin receptor and relieve the pain of oral cancer in rats within a certain period of time.