Endocannabinoid system is an important contributor to body’s immune responses which are significantly impaired by sleep deprivation (SD). Although cannabinoids can modulate the endocannabinoid system, but most are understudied, especially regarding SD. To investigate the therapeutic potential of CBD, CBG, CBC and their combinations, current study analyzed SD-induced memory impairment, depression, glial responses, and cytokine expression and therapeutic effects of cannabinoid treatments. The results showed that memory impairment and depression were more evident in SD groups. Moreover, microglial activation and proinflammatory polarization was also more evident and was supported by increased proinflammatory cytokine concentrations in SD groups. These changes were significantly reversed the cannabinoid groups but the combination of CBD+CBC was more effective than other treatments in revering these SD-induced behavioral and neuro-inflammatory changes.