Plant health is fundamental to global food security, ecosystem stability, and sustainable agriculture. However, plant diseases - exacerbated by climate change, globalization, and over-reliance on chemical control - pose escalating threats to crop productivity and food systems worldwide. In this context, Plant Growth-Promoting Fungi (PGPF) have been recognized as valuable biological agents in integrated plant disease management strategies. These beneficial fungi enhance plant resilience through multifaceted mechanisms, including antibiosis, mycoparasitism, competition for nutrients and niche space, induced systemic resistance (ISR), and direct growth promotion. Notably, genera such as Trichoderma, Penicillium, Piriformospora, and Fusarium have demonstrated efficacy in suppressing a wide range of plant pathogens, including fungi, bacteria, viruses, and nematodes, across diverse crops. By modulating host defense pathways, producing antimicrobial metabolites, and outcompeting pathogens in the rhizosphere, PGPF act as a “symbiotic shield” that supports plant health while minimizing chemical inputs. Despite their proven benefits, practical challenges such as strain specificity, environmental variability, formulation scalability, and regulatory constraints hinder large-scale adoption. This review synthesizes current knowledge on the ecological and molecular mechanisms underlying PGPF-mediated disease suppression, highlights their application across major crops, and discusses future prospects, including biotechnological enhancements and integration into sustainable farming systems. The strategic deployment of PGPF holds great promise for reducing pesticide dependency, enhancing crop resilience, and achieving long-term agricultural sustainability in alignment with One Health and global development goals.