Ingestion of monosodium glutamate (MSG) causes headache, nausea and craniofacial tenderness in healthy individuals. The present study explored whether MSG produces behavioural signs of headache, nausea and changes in craniofacial sensitivity in rats. The behavior of male and female Sprague Dawley rats was video recorded before and after intraperitoneal (i.p.) injections of either MSG (1-1000 mg/kg), nitroglycerin (GTN, 10 mg/kg) or normal saline. Behaviors (grimace score, head-flicks, rearing, head scratches, facial grooming, lying-on-belly and temporalis muscle region mechanical withdrawal threshold (MT)) were evaluated. Facial cutaneous temperature of the nose and forehead was measured before and after i.p. injections via infrared thermography. Plasma glutamate and calcitonin-gene related peptide (CGRP) concentrations after administration of 1000 mg/kg MSG were measured in anesthetized rats. MSG induced nocifensive, headache- and nausea-like behaviors in a dose-related manner but had no effect on MT. MSG (1000 mg/kg) induced a significantly greater frequency of headache-like behavior in females, but a longer duration of nausea-like behavior in males. MSG produced a prolonged increase in plasma glutamate and CGRP concentrations. Co-administration of the median effective dose of MSG (350 mg/kg) with GTN (10 mg/kg) amplified headache-like behaviors, induced significant craniofacial sensitivity and produced increased nausea-like behaviour. Co-administration of sumatriptan or naproxen with MSG (1000 mg/kg), significantly attenuated MSG-induced nocifensive and headache-like behaviors. Our data suggests that systemic administration of MSG to rats induces behavioral correlates of headache and nausea. This model may offer another avenue for research on the mechanism and treatment of primary headache disorders such as migraine.