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Gut microbial dysbiosis has been implicated in metabolic dysfunction-associated steatotic liver disease (MASLD) and diabetes, but the metabolic effects of candidate probiotic strains across this disease continuum remain incompletely understood. Based on the validation of disease-associated microbial patterns in a clinical cohort, Lactobacillus acidophilus as selected as a candidate strain, and its effects were systematically investigated across multiple complementary models, including Western diet, fructose-palmitate-cholesterol diet, high-fat diet, and leptin-deficient ob/ob mice. L. acidophilus supplementation attenuated hepatic steatosis and inflammatory injury in multiple complementary models and improved glucose tolerance in ob/ob mice. These effects were accompanied by reduced hepatic expression of pro-inflammatory cytokines, changes in AMPK-associated signaling, decreased expression of lipogenic (Srebf1 and Acc) and gluconeogenic (Pepck and G6pc) genes, and increased Ppara expression, suggesting coordinated regulation of glucose and lipid metabolism. Transcriptomic profiling further indicated that L. acidophilus influenced broader metabolic networks, including altered expression of Lpin1 and enrichment of pathways related to nutrient sensing and metabolic regulation. In addition, L. acidophilus supplementation altered gut microbial community structure in mouse models, while human cohort analyzes revealed context-dependent microbial patterns involving Lactobacillus, Akkermansia, and butyrate-producing Firmicutes across metabolic disease states. Collectively, these findings suggest that L. acidophilus may improve metabolic dysfunction through coordinated hepatic metabolic regulation and gut microbial modulation, supporting its potential as a probiotic candidate for MASLD and diabetes-associated metabolic disease.