The present study was designed to evaluate the antistress effect of Marsilea quadrifolia ethanolic extract in stress induced behavioural and physiological alteration in the mice. Anti-stress activity was evaluated using physical stress models viz. swimming endurance and post swimming motor function test, anoxic tolerance test and restraint stress test. Swiss albino mice (18-25 g) divided into four groups of six animals each were used for the study. Control group received CMC as vehicle and standard group received Withania somnifera (100 mg/kg) while Marsilea quadrifolia ethanolic extract (200 and 400 mg/kg) were administered orally for seven days. Change in immobility time in swim endurance and first clonic convulsion in anoxic tolerance test and stress-induced behavioral and biochemical alterations in immobilization stress was recorded as parameters. Marsilea quadrifolia ethanolic extracts significantly reduces the immobility timing along with increases the swimming endurance time, post motor function and clonic convulsion timing in anoxic tolerance test as compared to control group and significantly reversed the behavioral and biochemical alterations in restraint stress.