<p>Metabolic dysfunction-associated steatohepatitis (MASH) has become a global health issue associated with obesity and diabetes. It is becoming a leading cause of end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). Despite its increasing prevalence, effective pharmacotherapies for MASH remain limited, underscoring the urgent need for novel interventions. Amlexanox, an inhibitor of noncanonical IκB kinases, has demonstrated potential in restoring insulin sensitivity and glucose homeostasis in obese mice and human patients, as shown in our earlier studies. Here, we aimed to assess the therapeutic potential of amlexanox in dyslipidemia-associated diseases, particularly MASH and HCC, and to elucidate the underlying mechanism. We employed GAN diet-fed <i>Ldlr</i>^{<i>−/−</i>} mice, which simultaneously develop obesity, MASH, and atherosclerosis, to recapitulate human metabolic syndrome and associated complications. Amlexanox was administrated orally to these mice after disease onset to examine its therapeutic efficacy. Our study demonstrates that even a low dose of amlexanox significantly reversed MASH and nearly completely prevented the progression from MASH to HCC. Both phenotypic and transcriptomic studies revealed that amlexanox markedly improved MASH-related dyslipidemia, hepatic steatosis, inflammation, liver injury, and hepatic fibrosis. Furthermore, multi-omics analysis revealed that amlexanox enhances hepatic bile acid synthesis and promotes fecal bile acid excretion. Notably, amlexanox reprogrammed gut microbiota, robustly increasing the abundance of <i>Akkermansia muciniphila</i>, a probiotic known to improve metabolic dysfunction. These findings uncover the multifaceted therapeutic potential of amlexanox in treating MASH and atherosclerosis by targeting bile acid metabolism, gut microbiota, hepatic inflammation, and fibrosis. Our study highlights amlexanox as a promising candidate for clinical applications.</p>