Depression is a common debilitating disorder affecting over 300 million individuals worldwide, emphasizing the pressing need to develop novel treatment targets for this disorder. Nevertheless, the pathophysiology of this disorder remains incompletely elucidated, and the currently available antidepressant treatments are suboptimal in terms of their efficacy and delayed onset of action. Thus, identifying and exploring new therapeutic avenues is of paramount importance. Recent clinical and preclinical studies have demonstrated that numerous bitter taste receptor type 2 members (Tas2Rs) agonists, including epigallocatechin gallate (EGCG), resveratrol, caffeine, humulones, and berberine, can significantly alleviate depressive symptoms in both human patients and animal models of depression. However, the precise mechanisms underlying the antidepressant effects of Tas2Rs agonists remain largely unknown. Intriguingly, a growing body of evidence suggests that Tas2Rs agonists may modulate various signaling pathways and systems including neurotransmission, inflammation, brain-gut axis, and the blood-cerebrospinal fluid barrier, all of which are believed to be implicated in the pathophysiology of depression. Therefore, this review aims to provide a comprehensive overview of the potential mechanisms of Tas2Rs agonists in depression, It synthesizes current evidence regarding its involvement in neurotransmission, inflammation, brain-gut communication, blood-cerebrospinal fluid barrier function, and other relevant pathways. This review will not only provide a valuable foundation for future research on the therapeutic potential of Tas2Rs agonists for depressive disorders but also offer new insights into the understanding of the pathophysiology of depression and the development of novel treatment strategies for this disorder.