Nimesulide (NIM), an atypical non-steroidal anti-inflammatory drug (NSAID) is also used as analgesic. In the present study, we evaluated its effect on the prooxidant-antioxidant system of liver and the hepatoprotective potential of aqueous extract of the herb Phyllanthus niruri (PN) on NIM-induced oxidative stress in vivo using a murine model, by determining the activities of hepatic anti-oxidant enzymes superoxide dismutase (SOD) and catalase (CAT), levels of reduced glutathione (GSH) and lipid peroxidation (expressed as malonaldialdehyde, MDA). Aqueous extract of PN at a dose of 50 or 100 mg/kg body wt was administered either intraperitoneally or orally for 7 days, before NIM administration at a dose of 8 mg/kg body wt twice daily for 7 days in mice. Animals were sacrificed 24 h after administration of final dose of NIM. In another set of experiments, both aqueous extract of PN (at a dose of 50 or 100 mg/kg body wt) and NIM (8 mg/kg body wt) were administered simultaneously for 7 days. Animals were sacrificed 24 h after administration of final dose of the extract and NIM, liver tissues were collected, and the activities of SOD and CAT and levels of GSH and lipid peroxidation end-product (as MDA), were determined from the livers of all the experimental animals. Appropriate NIM control was maintained for all sets of experiments. NIM administration (8 mg/kg body wt) for 7 days caused significant depletion of the levels of SOD, CAT and reduced GSH, along with the increased levels of lipid peroxidation. Intraperitoneal administration of the extract at a dose of 50 mg/kg body wt for 7 days, prior to NIM treatment, significantly restored most of the NIM-induced changes and the effect was comparable to that obtained by administering 100 mg/kg body wt of the extract orally. Thus, results suggested that intraperitoneal administration of the extract could protect liver from NIM-induced hepatic damage more effectively than oral administration. Antioxidant property of the aqueous extract of PN was also compared with that of a known potent antioxidant, vitamin E. The PN extract at a dose of 100 mg/kg body wt along with NIM was more effective in suppressing the oxidative damage than the PN extract at a dose of 50 mg/kg body wt. Results suggested that beneficial effect of the aqueous extract of PN, probably through its antioxidant property, might control the NIM-induced oxidative stress in the liver.