Brewer’s spent grain, accounts for most of the solid residue left after beer production, yet its value is largely lost because high moisture causes rapid spoilage and limits storage. Despite its richness in proteins, dietary fibers, and bioactive compounds, BSG is commonly treated as low-value waste. This study investigates integrated stabilization and fermentation strategies to convert BSG into a stable and nutritionally enhanced raw material for feed, food, and bio-based applications within circular bio-economy frameworks. Five stabilization approaches (vacuum filtration, thin-layer air drying, natural drying, acid treatment, and alginate-based treatment) were comparatively evaluated in terms of physicochemical stability, nutrient retention, and microbiological safety. Alginate treatment, a food-grade and moderately cost-effective method, demonstrated superior preservation of proteins and fibers while enhancing structural integrity and shelf life. In contrast, natural drying resulted in greater nutrient degradation and variability. For biological upgrading, Saccharomyces cerevisiae was grown on BSG in both submerged (SmF) and solid-state (SSF) systems, the latter under aerobic and anaerobic conditions, with no external sugar supplementation. Fermentation increased protein content through microbial biomass synthesis and modified carbohydrate and fiber fractions. Although aerobic SSF achieved the highest protein enrichment, it showed increased susceptibility to filamentous fungal contamination. Anaerobic SSF provided a more balanced combination of nutritional enhancement, process stability, and industrial feasibility. These findings demonstrate that integrated stabilization–fermentation strategies offer an effective pathway for BSG valorization, supporting sustainable waste management and advancing circular bio-economy implementation in agro-industrial systems.