Background <p>This study aimed to examine the anti-inflammatory effects of esomeprazole (ESO) and fexuprazan (FEXU) in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and evaluated voltage-gated potassium channel 1.3 (Kv1.3) to infer the involved mechanism.</p> Methods <p>The production of nitric oxide (NO) and the expression of pro-inflammatory mediators and Kv1.3, influenced by ESO and FEXU, were measured by means of a quantitative analysis of NO production and by a quantitative real-time polymerase chain reaction (qRT-PCR), respectively. In addition, we assessed the inhibitory effects of ESO and FEXU on the activation of the mitogen-activated protein kinase (MAPK) signaling pathway by examining the phosphorylation states of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, via a Western blot analysis. We also investigated the effects of ESO and FEXU on macrophage polarization by evaluating the expressions of inducible nitric oxide synthase (iNOS) and cluster of differentiation (CD) 206 through immunocytochemistry (ICC) staining.</p> Results <p>The production of NO and the expression of pro-inflammatory mediators, as well as Kv1.3, were reduced by both ESO and FEXU. FEXU showed a greater inhibitory effect for pro-inflammatory mediators and Kv1.3. Both agents were found to suppress the activation of the MAPK signaling pathway, with FEXU reducing JNK and p38 phosphorylation and ESO reducing p38 phosphorylation. FEXU led to reduced iNOS expression with a consequent increase in CD206. In contrast, ESO did not induce significant changes in iNOS and CD206 expression levels.</p> Conclusion <p>These results suggest that FEXU has a superior anti-inflammatory effect relative to that of ESO, indicating its potential as an anti-inflammatory agent.</p>