Estradiol, the most potent estrogen, influences the serotonergic, dopaminergic, and glutamatergic systems in both sexes. It acts through estrogen receptors ERα, ERβ, and GPER, modulating neurotransmitter systems critical for learning, memory, reward, and sexual behavior. This review examines the role of estradiol in regulating these systems, highlighting its effects on neurotransmitter signaling pathways. Estradiol's impact is evident in rodent models, where hormone manipulations like gonadectomy alter neuronal circuits, linking hormonal fluctuations to neurotransmitter regulation. Estradiol exerts its effects through both genomic and non-genomic mechanisms, influencing gene expression and rapid signaling pathways. The review discusses the effects of estradiol on serotonin, dopamine, and glutamate systems, emphasizing the role of estrogen receptors in these processes. Findings suggest that estradiol and estrogen receptor agonists may offer therapeutic potential in neurological disorders. Despite limited human studies, the findings underscore the importance of translational research in bridging preclinical and clinical applications. The integration of evidence from neurotransmitter systems and receptor-specific effects enhances understanding of the neurobiological basis of brain function and pathophysiological mechanisms. The review highlights the complex relationship between estradiol and neurotransmitter systems, contributing to the field's advancement and future research on estradiol's role in neuronal circuits and brain disorders. Key findings include estradiol's role in serotonin synthesis, dopamine release, and glutamate regulation, with implications for mood, cognition, and neurological health. The review also discusses the interaction between estradiol and other hormones, emphasizing the complexity of hormonal interactions in brain function. Overall, the study provides a comprehensive overview of estradiol's impact on neurotransmitter systems, highlighting its significance in neurological and psychiatric conditions.Estradiol, the most potent estrogen, influences the serotonergic, dopaminergic, and glutamatergic systems in both sexes. It acts through estrogen receptors ERα, ERβ, and GPER, modulating neurotransmitter systems critical for learning, memory, reward, and sexual behavior. This review examines the role of estradiol in regulating these systems, highlighting its effects on neurotransmitter signaling pathways. Estradiol's impact is evident in rodent models, where hormone manipulations like gonadectomy alter neuronal circuits, linking hormonal fluctuations to neurotransmitter regulation. Estradiol exerts its effects through both genomic and non-genomic mechanisms, influencing gene expression and rapid signaling pathways. The review discusses the effects of estradiol on serotonin, dopamine, and glutamate systems, emphasizing the role of estrogen receptors in these processes. Findings suggest that estradiol and estrogen receptor agonists may offer therapeutic potential in neurological disorders. Despite limited human studies, the findings underscore the importance of translational research in bridging preclinical and clinical applications. The integration of evidence from neurotransmitter systems and receptor-specific effects enhances understanding of the neurobiological basis of brain function and pathophysiological mechanisms. The review highlights the complex relationship between estradiol and neurotransmitter systems, contributing to the field's advancement and future research on estradiol's role in neuronal circuits and brain disorders. Key findings include estradiol's role in serotonin synthesis, dopamine release, and glutamate regulation, with implications for mood, cognition, and neurological health. The review also discusses the interaction between estradiol and other hormones, emphasizing the complexity of hormonal interactions in brain function. Overall, the study provides a comprehensive overview of estradiol's impact on neurotransmitter systems, highlighting its significance in neurological and psychiatric conditions.