Previous study showed the up-regulated expression of the Ca²⁺-activated K⁺ channel K_Ca3.1 in inflammatory CD4⁺ T cells has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Histone deacetylases (HDACs) are involved in intestinal inflammation, and HDAC inhibitors such as vorinostat ameliorate autoimmune colitis. In the present study, we examined the involvement of HDACs in the up-regulation of K_Ca3.1 in the CD4⁺ T cells of IBD model mice. The expression levels of K_Ca3.1 and its transcription regulators were quantitated using a real-time PCR assay, Western blotting, and depolarization responses induced by the selective K_Ca3.1 blocker TRAM-34 (1 μM) were measured using a voltage-sensitive fluorescent dye imaging system. The treatment with 1 μM vorinostat, a pan-HDAC inhibitor, for 24 hr repressed the transcriptional expression of K_Ca3.1 in the splenic CD4⁺ T cells of IBD model mice. Accordingly, TRAM-34-induced depolarization responses were significantly reduced. HDAC2 and HDAC3 were significantly up-regulated in the CD4⁺ T cells of IBD model mice. The down-regulated expression of K_Ca3.1 was observed following treatments with the selective inhibitors of HDAC2 and HDAC3. Taken together, The K_Ca3.1 K⁺ channel regulates inflammatory cytokine production in CD4⁺ T cells, mediating epigenetic modifications by HDAC2 and HDAC3.