In Sri Lankan traditional medicine, the endemic plant Vernonia zeylanica (L.) Less (Asteraceae) is recommended for the treatment of boils and bone fractures. A strong possibility thus exists that this plant could possess antinociceptive activity, but this has not been scientifically tested. The aim of this study was to investigate the antinociceptive potential of aqueous stem extract (ASE) of V. zeylanica in rats using two models of nociception (hot-plate and tail-flick tests) and different concentrations (750, 1500, and 2500 mg=kg, given orally). The results showed that ASE possessed marked and significant (p < 0.05) antinociceptive activity (in terms of prolongation of reaction time) when evaluated in the hotplate test but not in the tail-flick test. The antinociceptive action had rapid onset (within 1 h) and moderately long duration of activity (up to 3 h), but was 2-to 5-fold weaker than morphine. Further, the ASE significantly suppressed the number of paw lickings and the time spent on paw licking in both phases of the formalin test. Naloxone, an opioid receptor antagonist, blocked the antinociceptive activity of ASE. Collectively, these observations suggest that ASE-induced antinociception was mediated centrally at the supraspinal level via opioid receptor mechanisms and is also effective against neurogenic and inflammatory pain. The ASE had mild antioxidant and moderate sedative actions, which are likely to contribute to its antinociceptive action. The ASE is well tolerated (in terms of overt signs, or renal, hepatic, or hemotoxicities) and nontoxic (by brine shrimp lethality assay). Phytochemical analysis revealed the presence of alkaloids, phenols, and steroids, which could contribute to the antinociceptive action. It is concluded that ASE of V. zeylanica has safe and moderate oral antinociceptive action.