Several studies have shown that up-regulation of K_2P5.1 K⁺ channel in CD4⁺ T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA) and a mouse model of inflammatory bowel disease (IBD). However, the underlying mechanism of K_2P5.1 up-regulation in T cells remains to be elucidated. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, and T cells are exposed to hypoxic environment during recruitment from the inflamed tissues to secondary lymphoid tissues. Here we explored whether inflammation-associated hypoxia is attributable to increased expression and activity of K_2P5.1 in splenic CD4⁺ T cells of chemically-induced IBD model mice. Significant increase in hypoxia-inducible factor (HIF)-1α transcripts and proteins was found in splenic CD4⁺ T cells of IBD model. In activated splenic CD4⁺ T cells, hypoxia (1.5% O₂) increased K_2P5.1 expression and activity, whereas, the treatment with the HIFα subunit inhibitor, FM19G11 decreased them. Together, these results provide the possible mechanism for K_2P5.1 up-regulation via HIF-1α signal activation in CD4⁺ T cells of IBD model.