The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here, we demonstrate that mice lacking cannabinoid receptor type 1 (CB1^-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1^-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared to wild-type (CB1^+/+) littermates. Moreover, CB1^-/--derived pituitary cells respond with a significantly higher corticotropin (ACTH) secretion to CRH and forskolin challenges as compared to pituitary cells derived from CB1^+/+ mice. Both CB1^-/- and CB1^+/+ mice properly respond to a high dose dexamethasone test, but response to low dose dexamethasone is influenced by genotype. In addition, CB1^-/- mice show increased CRH mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus, but not in other extra-hypothalamic areas, such as the amygdala and the piriform cortex, where CB1 and CRH mRNA have been co-localized. Finally, CB1^-/- mice have selective glucocorticoid receptor (GR) mRNA down-regulation in the CA1 region of the hippocampus, but not in the dentate gyrus or PVN. Conversely, mineralocorticoid receptor (MR) mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.