Problem of sleep deprivation or inadequate sleep is seen more frequently now-days. Sleep loss or inadequate quality sleep is considered as health risk factor that contributes to the genesis of several disease processes. Sleep deprivation has recently been proposed to cause oxidative damage. In the present study, we investigated the possible involvement of GABAergic modulation in the protective effect of zolpidem against sleep deprivation-induced behavior alterations and oxidative damage in mice. 72-hr sleep deprivation caused anxiety like behavior, weight loss, impaired ambulatory activity and oxidative damage as indicated by increased lipid peroxidation, nitrite level and depletion of reduced glutathione and catalase activity as compared to naïve animals (placed on saw dust). Treatment with Zolpidem (5 mg/kg and 10 mg/kg, ip) significantly improved ambulatory activity, weight loss and antianxiety effect as compared to control (sleep deprived) P<0.05. Biochemically, Zolpidem treatment significantly restored depleted reduced glutathione, catalase activity, attenuated lipid peroxidation and nitrite level as compared to control (72-hr sleep-deprived) (P<0.05). A combination flumazenil (0.5 mg/kg) and picrotoxin (0.5 mg/kg) with lower dose of zolpidem (5 mg/kg) significantly antagonized the protective effect of zolpidem (P<0.05). However, combination of muscimol (0.05 mg/kg) with zolpidem (5 mg/kg, ip) potentiated protective effect of zolpidem which was significant as compared to their effect per se (P<0.05). Present study suggests that zolpidem might produce its protective effect by involving GABAergic system against sleep deprivation-induced behavior alterations and related oxidative damage.