Cannabis sativa (CS) has been identified as critical signals of the intricate network that control male and female reproduction, at different stages, with direct effects on gonads, and having target on both the hypothalamus and the pituitary (Schuel and Burkman, 2005). After tobacco and alcohol, marijuana is the most commonly abused substance by women of childbearing age (NSDUH, 2013). Cannabis ingestion has been associate with low birth weight, intrauterine growth retardation, presence of congenital abnormalities, prenatal death and delayed the time of commencement of respiration (Gibson et al., 1983; Sherwood et al., 1999). It has been reported that cannabinoid receptors (CBRs) 1 and 2 are well expressed in the mammalian ovaries (EL-Talatini et al., 2009). However, no study has investigated the influence of melatonin on cannabinoid-induced female reproductive hormones in human or animal models. Fifty five female wistar rats were randomised to 11 groups (n=5 rats each) as follows: Groups I-XI (n=5 rats each) received normal saline (1 ml), ethanolic extract of cannabis sativa (EECS) (2.00mg/kg), EECS+melatonin (4.00 mg/kg), melatonin, cannabinoid receptor blocker 1 (CBRB1) (rimonabant hydrochloride) (2.00mg/kg), cannabinoid receptor blocker 2 (CBRB2) (am630) (2.00mg/kg), CBRB1 +EECS, CBRB2 +EECS, CBRB1 +CBRB2 +EECS, CBRB1 +EECS+melatonin, CBRB2 + EECS +melatonin respectively orally for 2 weeks. Gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E), progesterone and prolactin were measured using standard methods. Values were expressed as means ± S.E.M., compared by ANOVA. Cannabis sativa significantly (p<0.05) decreased GnRH, FSH, LH, E, progesterone and prolactin levels respectively. However, cannabinoid receptors 1 and 2 when blocked separately, significantly (p<0.05) increased the levels of all these reproductive hormones compared to CS-treated rats but decreased significantly (p<0.05) when compared to the control, though that of former is more than the latter. All these effects were ameliorated by melatonin when the cannabiniod receptors (CBRs) were stimulated and blocked. This study showed that the gonadotoxic effects of CS could be mediated by endocrine disruption through the use of both cannabinoid receptors 1 and 2, though that of CBRB2 is more than that of CBRB1. However, the gonadotoxic effects of CS could be ameliorated by melatonin.