Abstract: Epilepsy and autism spectrum disorder (ASD) are highly mutually comorbid, suggesting potential overlaps in genetic etiology, pathophysiology, and neurodevelopmental abnormalities. Adenosine, an endogenous anticonvulsant and neuroprotective neuromodulator of the brain, has been proved to affect the process of epilepsy and ASD. On the one hand, adenosine plays a crucial role in preventing the progression and development of epilepsy through adenosine receptor-dependent and -independent ways. On the other hand, adenosine signaling can not only regulate core symptoms but also improve comorbid disorders in ASD. Given the important role of adenosine in epilepsy and ASD together, therapeutic strategies related to adenosine, including the ketogenic diet, neuro-modulation therapy, and adenosine augmentation therapy, have been suggested for the arrangement of epilepsy and ASD. There are several proposals in this review. Firstly, based on the comorbid symptoms and mechanisms of epilepsy and ASD, to further discuss the relationship between both diseases. Secondly, to explore the role of adenosine involved in epilepsy and ASD. Lastly, to emphasize the potential therapeutic value and clinical approaches of adenosine-related therapies in treating epilepsy and ASD.