The transition toward sustainable agro-food systems has intensified interest in plant-based foods as primary protein sources, yet their nutritional efficacy is constrained by anti-nutritional factors, limited digestibility, and safety concerns. Fermentation optimization represents a critical biotechnological intervention to address these limitations through precise parameter control. This review examines the mechanistic roles of key fermentation parameters—including temperature, pH dynamics, inoculum size, fermentation time, moisture content, and oxygen availability—in modulating biochemical transformations within cereals, legumes, oilseeds, and tubers. Parameter optimization enhances protein digestibility through proteolytic degradation, reduces phytates and tannins via microbial enzyme activity, improves mineral bioavailability, and facilitates vitamin biosynthesis. Concurrently, controlled fermentation achieves mycotoxin reduction, pathogen inhibition through organic acid production, and biogenic amine mitigation. Advanced optimization methodologies, including response surface methodology, artificial neural networks, and predictive modeling, enable multi-factorial parameter integration for industrial scalability. The application of optimized fermentation within sustainable agro-food systems contributes to post-harvest loss reduction, circular bioeconomy principles, and climate-resilient food processing. Current challenges include raw material variability, strain inconsistency, and regulatory standardization. Future directions encompass omics-guided fermentation optimization, precision starter culture development, and digital fermentation platforms. This review establishes that systematic parameter optimization is essential for realizing the nutritional and safety potential of fermented plant-based foods within sustainable agricultural frameworks.