ABSTRACTThe co‐expression of different types of G protein‐coupled receptors (GPCRs) in the same cells can have implications for receptor signaling and receptor cross‐talk, potentially altering the apparent potency or efficacy of ligands targeting each receptor. The endocannabinoid and orexinergic systems, consisting of class A GPCRs and their endogenous ligands, are highly complex and regulate processes such as appetite, sleep, nociception, and energy homeostasis. The shared anatomical distribution of cannabinoid and orexin receptors in various regions of the central nervous system (CNS), coupled with data from previous studies exploring physical and functional interactions between these receptors, suggests that the endocannabinoid and orexinergic systems engage in crosstalk. In this study, we explored how orexin receptors (OX1, OX2) altered the in vitro signaling of cannabinoid receptors (CB1, CB2) in Chinese hamster ovary (CHO)‐K1 cells by quantifying cyclic adenosine monophosphate (cAMP) inhibition and βarrestin2 recruitment. Our results suggest that orexin receptors alter agonist‐dependent signaling at the cannabinoid receptors by enhancing cannabinoid receptor‐mediated cAMP inhibition while increasing or decreasing cannabinoid receptor‐mediated βarrestin2 recruitment. These initial results are important for understanding the effects associated with cannabinoid ligands and may provide novel insights for therapeutics targeting physiological processes modulated by both systems.