The present study was undertaken to investigate the neuro-protective effects of L-carnosine and exercise against the hippocampal neuronal death secondary to Kainic acid-induced seizure in mice by measuring seizure activity and nNOS, Caspase-3, BDNF, NGF protein expression. A total of 28 mice were randomly assigned to the following treatment groups; control (N=7), carnosine supplement (N=7), exercise (N=7), carnosine supplement+exercise (N=7), of which each regimen lasted for 8 weeks. With respect to seizure activity, a significant time by treatment interaction (p=<.01) showed that either Ca+KA (p=.984) or EX+KA (p=.823) or Ca+Ex+KA (p=.000) had a significantly lower seizure activity than KA. Further, the Ca+EX+KA group had a significantly lower seizure activity than either the Ca+KA (p=.000) or EX+KA (p=.002) group. Similar time by treatment interactions were found in nNOS (p=.000), NGF protein expression (p=.001), and BNDF protein expression (p=.001) such that either Ca+KA or EX+KA or Ca+EX+KA had significantly higher levels of NGF and BDNF protein expression but a lower level of nNOS protein expression than the KA. Further, the Ca+EX+KA group had significantly higher NGF and BDNF protein expression but a lower Nnos protein expression than either the Ca+KA or EX+KA. The present findings suggest that the combined treatment of Ca and Ex, compared to either Ca or Ex, has a greater protective effect against the hippocampal neuronal death secondary to Kainic acid-induced seizure.