Abstract Context: Syzygium cumini (L.) Skeels (Myrtaceae) is a tree with dark purple fruits, popularly known as "jambolão" or "jambolan". In folk medicine, this plant is used for the treatment of diabetes and inflammatory conditions. Objective: We investigated the antinociceptive effect of ethanol extract (EE) from S. cumini leaves on orofacial nociception. Material and methods: The antinociceptive effects of the EE obtained from the leaves of S. cumini were evaluated in mice using formalin- and glutamate-induced orofacial nociception. Results: ESI-MS/MS analyses demonstrated that major constituents in the analyzed samples coincided with the mass of the phenolic acids and flavonoids. In pharmacological approach, pre-treatment with EE (100, 200, or 400 mg/kg, p.o.) significantly reduced (p < 0.05 or p < 0.01) the percentage of paw licks time during phase 2 (43.2, 47.1, and 57.4%, respectively) of a formalin pain test when compared to control group animals. This effect was prevented by pretreatment with glibenclamide and N(G)-nitro-l-arginine (l-NOARG). The extract, all doses, also caused a marked inhibition (p < 0.01 or p < 0.001) of glutamate-induced orofacial nociception (38.8, 51.7, and 54.7%) when compared with the control group. No effect was observed with the rota-rod model. Conclusions: We can suggest that the antinociceptive effect of the EE is mediated by peripheral mechanisms, possibly involving KATP channels and the nitric oxide pathways. These effects appear to be related to the presence of flavonoids compounds, such as quercetin.