Plant diseases are still the main problem for the reduction in crop yield and a threat to global food security. Additionally, excessive usage of chemical inputs such as pesticides and fungicides to control plant diseases have created another serious problem for human and environmental health. In view of this, the application of plant growth-promoting rhizobacteria (PGPR) for controlling plant disease incidences has been identified as an eco-friendly approach for coping with the food security issue. In this review, we have identified different ways by which PGPRs are capable of reducing phytopathogenic infestations and enhancing crop yield. PGPR suppresses plant diseases, both directly and indirectly, mediated by microbial metabolites and signaling components. Microbial synthesized anti-pathogenic metabolites such as siderophores, antibiotics, lytic enzymes, hydrogen cyanide, and several others act directly on phytopathogens. The indirect mechanisms of reducing plant disease infestation are caused by the stimulation of plant immune responses known as initiation of systemic resistance (ISR) which is mediated by triggering plant immune responses elicited through pathogen-associated molecular patterns (PAMPs). The ISR triggered in the infected region of the plant leads to the development of systemic acquired resistance (SAR) throughout the plant making the plant resistant to a wide range of pathogens. A number of PGPRs including Pseudomonas and Bacillus genera have proven their ability to stimulate ISR. However, there are still some challenges in the large-scale application and acceptance of PGPR for pest and disease management. Further, we discuss the newly formulated PGPR inoculants possessing both plant growth-promoting activities and plant disease suppression ability for a holistic approach to sustaining plant health and enhancing crop productivity.