Male Wistar rats were subjected to chronic restraint stress (CRS; 6 h/day for 21 days) alone or along with either hydroalcoholic extract of Ocimum sanctum (Os; 100 mg/kg; orally) or MK-801, an NMDA receptor antagonist (0.3 mg/kg; i.p.). In the rats subjected to only CRS, plasma cAMP level was significantly raised on day 21, with no significant change in plasma corticosterone level. There was a significant (p < 0.05) fall in myocardial glutathione level, along with a significant (p < 0.05) rise in myocardial superoxide dismutase (SOD) and catalase activities, while light microscopy showed evidence of myocardial edema. Both Os and MK-801 significantly prevented the CRS-induced rise in plasma cAMP level, myocardial SOD and catalase activities as well as the light microscopic changes in the myocardium. This study revealed that Ocimum sanctum protects rat heart from chronic restraint stress induced changes, through its central effect.