The central nervous system is one of the most vulnerable organs affected by mercury toxicity. Both acute and chronic exposure to mercury is also known to cause a variety of neurological or psychiatric disorders. Here, the neuroprotective effect of berberine (BN; 100 mg/kg bwt) on mercuric chloride (HgCl2; 0.4 mg/kg bwt) induced neurotoxicity and oxidative stress was examined in rats. Adult male albino Wistar rats were injected with HgCl2 for 7 days. HgCl2 treatment induced oxidative stress by increasing lipid peroxidation (LPO) and nitrite/nitrate (nitric oxide; NO) production along with a concomitant decrease in glutathione (GSH) and various antioxidant enzymes, namely superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. Pre-treatment of rats with BN inhibited LPO and NO production, whereas it increased GSH content. Activities of antioxidant enzymes were also restored concomitantly when compared to the control rats after BN administration. Berberine also caused decrease in TNF-α level and caspase-3 activity which was higher with HgCl2. Furthermore, treatment with BN inhibited apoptosis, as indicated by the reduction of Bax/Bcl-2 ratio in brain tissue. These data indicated that BN augments antioxidant defense with anti-inflammatory and anti-apoptotic activities against HgCl2-induced neurotoxicity and provides evidence that it has a therapeutic potential as neuroprotective agent.