The recovery of strategic metals (Sc, REEs, etc.) from red mud, a highly alkaline industrial solid waste, is severely hindered by silicate encapsulation and silica gelation during acid leaching. This study proposes a bio-desilication pretreatment using an acclimated strain of Bacillus mucilaginosus to address these challenges. Under optimized bio-desilication conditions, silicon leaching and desilication rates of 58.3% and 62.6% were achieved, respectively. Mechanistic investigations revealed that bacterial cells and their metabolites (organic acids and EPS) preferentially attack defect sites in aluminosilicate minerals, disrupting the Si–O network and liberating Si4+ and Al3+ ions, thereby driving extensive phase reconstruction, including dissolution of aluminosilicates (e.g., kaolinite, cancrinite), enrichment of stable minerals (e.g., hematite, rutile), and precipitation of secondary phases (e.g., calcite, calcium oxalate). This significantly enhanced subsequent metal leaching efficiencies in sulfuric acid, nitric acid, phosphoric acid, and Aspergillus niger bioleaching systems, with improvements ranging from 44.3% to 273%, while effectively suppressing silica gel formation. A preliminary economic analysis indicates a net benefit of ¥1,650 per ton of red mud, highlighting the potential of this sustainable bio-desilication strategy for valorizing silicate-bearing alkaline solid wastes.