Plant growth-promoting rhizobacteria (PGPR) play a crucial role in enhancing plant defense by activating systemic resistance against a broad range of pathogens. This review explores the molecular basis of PGPR-mediated induced systemic resistance (ISR), with particular emphasis on defense signaling pathways regulated by jasmonic acid, ethylene, and salicylic acid. The induction of ISR involves multiple mechanisms, including the regulation of plant hormone signaling, synthesis of antimicrobial metabolites, and priming of plant defense systems. As a result, plants exhibit increased expression of defense-related genes and a strengthened immune response. A clear understanding of these molecular interactions is essential for promoting sustainable agricultural strategies and minimizing dependence on chemical pesticides. Recent progress in omics-based approaches and bioinformatic tools has significantly improved our understanding of PGPR-plant interactions, facilitating the discovery of new bacterial strains and key signaling components. Future studies should emphasize the integration of multi-omics data with field-based research to enhance the effective application of PGPR for improved crop protection and productivity.