Sulfamethoxazole (SMX) is the most commonly used antibiotics in China for inhibiting aquatic animal diseases. However, the residues of SMX are difficult to eliminate and may enter the food chain, leading to considerable threats on human health. The bacterial strain Sphingobacterium mizutaii LLE5 was isolated from activated sludge. This strain could utilize SMX as its sole carbon source and degrade it efficiently. Under optimal degradation conditions (30.8 °C, pH 7.2, and inoculum amount of 3.5 × 107 cfu/mL), S. mizutaii LLE5 could degrade 93.87% of 50 mg/L SMX within 7 days. Four intermediate products from the degradation of SMX were identified: sulfanilamide, 4-aminothiophenol, 5-amino-3-methylisoxazole, and aniline, suggesting a possible degradation pathway based on these findings. This report is the first to confirm that Sphingobacteriumi could degrade SMX. Furthermore, S. mizutaii LLE5 could also degrade other sulfonamides. The degradation efficiencies of strain LLE5 for sulfadiazine, sulfaguanidine, sulfamisoxazole, and sulfadimidine were 59.85%, 51.68%, 46.95%, and 37.42%, respectively.