The effects of trans-resveratrol (1) were evaluated in acute nociception models induced by capsaicin or glutamate in mice, in an attempt to further characterize its mechanism of action. The oral administration of 1 (50 and 100 mg/kg) reduced significantly the licking behavior elicited by capsaicin (1.6 μg/paw) or glutamate (10 μmol/paw). The co-administration of 1 into the mouse paw (200 μg/site) markedly prevented glutamate-induced licking, without affecting capsaicin responses. In addition, the intrathecal (it) injection of 1 (150 to 600 μg/site) greatly reduced the licking behavior caused by capsaicin, but not glutamate. Similarly, the intracerebroventricular injection of 1 (300 μg/site) caused a potent inhibition of capsaicin-induced nociception, while the glutamate responses remained unaffected. However, the co-administration of 1 (300 μg/site) reduced the biting behavior induced by spinal injection of glutamate (30 μg/site, it), leaving capsaicin (6.4 μg/site)-induced biting unaltered. Notably, the oral administration of 1 (100 mg/kg) inhibited significantly the capsaicin-induced increase of c-Fos and COX-2 labeling in the spinal cord and COX-2 expression in the cortex, but failed to affect c-Fos and COX-2 expression in the glutamate model. This study has explored the effects of 1 in both the capsaicin and glutamate models, extending current knowledge on the analgesic effects of trans-resveratrol.