Pediococcus pentosaceus (P. pentosaceus) is a lactic acid bacterium widely distributed in fermented foods, dairy products, human specimens, and animal-associated environments. In recent years, P. pentosaceus has attracted considerable attention as a potential probiotic candidate due to its intestinal adaptability, antibacterial activity, antioxidant capacity, immunomodulatory effects, and ability to regulate host–microbiota interactions. However, existing findings remain inconsistent, and its systemic therapeutic value has yet to be comprehensively evaluated from the perspectives of strain specificity and translational medicine. This review examines the probiotic characteristics, oral safety, and potential mechanistic applications of P. pentosaceus in systemic diseases. Current evidence suggests that different strains may exert beneficial effects through multiple interrelated mechanisms, including enhanced intestinal colonization, production of exopolysaccharides (EPS) and bacteriocins, regulation of short-chain fatty acids (SCFAs), restoration of intestinal barrier integrity, inhibition of inflammatory signaling pathways, modulation of oxidative stress, and alteration of bile acid and other microbial metabolite profiles. These mechanisms are associated with potential benefits across hepatobiliary, gastrointestinal, metabolic, respiratory, neurological, and inflammation-related conditions. However, most current evidence derives from in vitro experiments or animal models, clinical evidence remains limited and frequently based on multi-strain formulations, and considerable variability exists across studies in strain origin, dosage, intervention duration, outcome measures, and safety assessment methods. Findings from individual strains should therefore not be extrapolated to the species as a whole. Overall, P. pentosaceus represents a promising but insufficiently validated probiotic candidate for adjunctive disease management, and future research should prioritize standardized strain characterization, causal mechanism validation, dose-response assessment, long-term oral safety evaluation, and well-designed single-strain clinical trials.