Glutamate excitotoxicity is mediated by intracellular Ca2+ overload, caspase‐3 activation, and ROS generation. Here, we show that curcumin, tannic acid (TA) and (+)‐catechin hydrate (CA) all inhibited glutamate‐induced excitotoxicity. Curcumin inhibited PKC activity, and subsequent phosphorylation of NR1 of the NMDA receptor. As a result, glutamate‐mediated Ca2+ influx was reduced. TA attenuated glutamate‐mediated Ca2+ influx only when simultaneously administered, directly interfering with Ca2+. Both curcumin and TA inhibited glutamate‐induced caspase‐3 activation. Although Ca2+ influx was not attenuated by CA, caspase‐3 was reduced by direct inhibition of the enzyme. All polyphenols reduced glutamate‐induced generation of ROS.