The present study was undertaken to evaluate antistress and immunomodulatory activity of aqueous extract of Momordica charantia (MC). Antistress activity was evaluated by measuring the swimming time in mice and cold immobilization induced stress for 10 days in rats, using Withania somnifera (100mg/kg) as reference standard. Immunomodulatory activity was evaluated by carbon clearance assay and percentage adhesion of neutrophils to nylon fibers using Levamisole as reference standard. The degree of protection was determined by measuring gastric ulceration, adrenal gland and spleen weights and by measuring levels of serum glucose, AST and ALT. Swiss albino mice of either sex were divided into 4 groups such as normal control, MC lower dose (450 mg/kg, p.o), MC higher dose (900 mg/kg, p.o) and standard group, treated with standard drug Levamisole (50 mg/kg, p.o). MC increased the swimming time in mice significantly (P<0.001) and the results are comparable to that of standard Withania somnifera. MC has also significantly (P<0.001) reversed the cold immobilization induced changes in glucose, AST, ALT, ulcer score, weight of adrenal gland and spleen. MC improves the phagocytic index in a dose dependent manner. MC at higher dose significantly (P<0.001) increased the percentage of adhesion of Neutrophils to nylon fibers when compared with the normal control animals. The results were comparable with that of standard drug levamisole. Momordica charantia has significant antistress, immunomodulatory activity.