Small- and intermediate-conductance Ca²⁺-activated K⁺ channels, K_Ca2.3 and K_Ca3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. K_Ca2.3 and K_Ca3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates K_Ca2.3 and K_Ca3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via K_Ca2.3- and K_Ca3.1-mediated pathways in high-fat diet (HFD)- or thioacetamide-induced liver disease models in mice. Modafinil was administered orally in the form of a racemate, (R)-isomer, or (S)-isomer. We also determined whether the treatment targeted the profibrotic activity of hepatic stellate cells using immortalized human hepatic stellate cells (LX-2 cells). Modafinil improved HFD- or thioacetamide-induced changes compared to the control, leading to a reduced inflammatory response, collagen deposition, and α-smooth muscle actin expression both in vivo and in vitro. However, modafinil did not relieve HFD-induced steatosis. There were no significant differences in the effects of the (R)- and (S)-isomers of modafinil. K_Ca2.3 and K_Ca3.1 were upregulated and catalase was downregulated in liver tissues from thioacetamide- or HFD-induced liver disease models or in TGF-β-treated LX-2 cells. TGF-β-induced upregulation of K_Ca2.3, K_Ca3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against K_Ca2.3 or K_Ca3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via K_Ca2.3- and K_Ca3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting K_Ca2.3- and K_Ca3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.