As an important biomass material, bamboo is susceptible to fungal infection during use, leading to severe deterioration. The white-rot fungus Schizophyllum commune is one of the world’s most widely distributed fungi, which preferentially colonizes dead or senescent bamboo tissues. However, the mechanism of the influence of the S. commune infection on the mechanical and chemical properties of bamboo remains unexplored. This research systematically examined the temporal effects (0, 30, 60, and 90 days) of S. commune QP33 infection on bamboo’s mechanical properties and chemical composition using various characterization methods. Results showed that S. commune QP33 secreted key lignin-modifying enzymes (laccase and lignin peroxidase) and hemicellulases (xylanase). Mass loss of bamboo increased progressively with infection time, reaching 13.33% after 90 days. Decayed bamboo showed distinct mechanical deterioration patterns, including a sharp initial drop in bending strength and a continuous decline in tensile strength. Microstructural and chemical analyses revealed that the fungus preferentially degraded lignin and hemicellulose. This selective degradation led to cell wall delamination and pore formation, ultimately causing the observed macroscopic mechanical deterioration. Our study provides critical insights into the biodeterioration mechanism of bamboo by S. commune and offers valuable guidance for bamboo preservation and high-value utilization.