Background: : Major depressive disorder (MDD) is a prevalent neuropsychiatric disease that carries a staggering global burden. Although numerous antidepressants are available on the market, unfortunately, many patients die by committing suicide as a result of the therapeutic lag between treatment initiation and the improvement of depressive symptoms. This therapeutic lag highlights the need for new antidepressants that provide rapid relief of depressive symptoms. Method: : In this review, we discuss the seminal researches on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in animal models of depression and highlight the substantial evidence supporting the development of rapid-acting antidepressants targeting HCN channels. Results: : HCN channels are associated with the risk of depression and targeting HCN channels or its auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) function may exert a rapid anti-depressant-like effect. Conclusions: : Compounds acting on HCN subunits or the TRIP8b-HCN interaction site may be excellent candidates for development into effective drugs with rapid antidepressant action.