Serotonin, a neurotransmitter crucial for brain development and neuronal activity, regulates the activation states of glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. GSK3, in turn, directly interacts with serotonin receptors, particularly the serotonin 1B receptor, modulating its activity. This review highlights the role of GSK3 as an intermediate modulator in serotonin neurotransmission, emphasizing its importance in maintaining balanced serotonin-regulated brain function and behaviors. Several classes of serotonin-modulating drugs, such as antidepressants and atypical antipsychotics, regulate GSK3 activity, underscoring its potential as a therapeutic target in neuropsychiatric diseases associated with abnormal serotonin function. The review also discusses the specific mechanisms by which GSK3 regulates serotonin receptor signaling and the impact of GSK3 inhibitors on serotonin receptor-mediated physiological and behavioral functions.Serotonin, a neurotransmitter crucial for brain development and neuronal activity, regulates the activation states of glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. GSK3, in turn, directly interacts with serotonin receptors, particularly the serotonin 1B receptor, modulating its activity. This review highlights the role of GSK3 as an intermediate modulator in serotonin neurotransmission, emphasizing its importance in maintaining balanced serotonin-regulated brain function and behaviors. Several classes of serotonin-modulating drugs, such as antidepressants and atypical antipsychotics, regulate GSK3 activity, underscoring its potential as a therapeutic target in neuropsychiatric diseases associated with abnormal serotonin function. The review also discusses the specific mechanisms by which GSK3 regulates serotonin receptor signaling and the impact of GSK3 inhibitors on serotonin receptor-mediated physiological and behavioral functions.