BACKGROUND Smilax glabra Roxb. is a traditional Chinese herb, the rhizome of Smilax glabra has been used in folk medicine for the treatment of lead poisoning. OBJECTIVE The present study was conducted to investigate the protective role of Smilax glabra extract (SGE) individually or combined with meso-2,3-dimercaptosuccinic acid (DMSA) against the effects of lead acetate on oxidative stress and lead burden in rats. METHODS The biochemical parameters and enzymes in different treated rats were determined by commercial kits. The metal concentrations were measured using atomic absorption spectrophotometer. RESULTS SGE (300 mg/kg) showed very low toxicity to organs in non-lead exposed rats. Administration of SGE individually had no effect on blood zinc protoporphyrin (ZPP) level but significantly enhanced the glutathione (GSH) content and delta-aminolevulinic acid dehydratase (ALAD), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activities in lead exposed rats. The co-treatment of SGE and DMSA had a synergism in increasing brain, liver and kidney superoxide dismutase (SOD), catalase (CAT) activities and GSH level, and decreasing oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS) levels. Moreover, the co-treatment could improve the hepatic and renal histopathology changes. SGE as chelating agent showed significant efficiency in reducing blood and tissue lead burden. CONCLUSIONS The in vivo results suggested that SGE individually or combined with DMSA exhibited remarkable protective effects on lead-induced oxidative stress and lead burden in rats.