Astroglial potassium channels (Kir4.1) are involved in the onset of depression. Previous study showed that Kir4.1 channel is upregulated in the lateral habenula in rat models of depression (Nature, 554(7692), 323-327, 2018). In addition, it is reported that serotonin reuptake inhibitors (e.g., SSRIs) inhibit Kir4.1 channel currents, suggesting that astroglial Kir4.1 channels might be involved in the pharmacological action of antidepressants. In this study, to explore the role of Kir4.1 channels in the treatment of depression, we evaluated the effects of the Kir4.1 channel inhibitors, VU0134992 and quinacrine, on lipopolysaccharide (LPS)-induced depression in mice using forced swim test. First, treatments of mice with VU0134992 (10–30 mg/kg, s.c.) and quinacrine (10-100 mg/kg, s.c.) reduced immobility time in despaired model by forced swimming. Next, we observed that LPS (0.8 mg/kg, i.p.) increased immobility time in the forced swim test, and the immobility time was dose-dependently reversed by quinacrine (30-100 mg/kg, s.c.). Especially, quinacrine (100 mg/kg, s.c.) significantly attenuated prolonged immobility time by LPS in forced swim test. Furthermore, quinacrine (100 mg/kg, s.c.) also significantly improved LPS-induced anxiety like behavior in the elevated plus maze test. These results demonstrated that Kir4.1 channel inhibitors have antidepressant effects, suggesting that the Kir4.1 channel inhibitors are useful as new antidepressants.