Abstract: To address the problems of sediment degradation and water quality deterioration caused by combined pollution of nitrogen (N), phosphorus (P), and antibiotics in aquaculture systems, this study established an outdoor microcosm simulation system to investigate the synergistic mechanisms of Maifanite and Vallisneria natans in efficiently purifying aquaculture tailwater and remediating sediment internal loading. The results showed that the combined Maifanite and V. natans treatment group (MFVS) exhibited excellent nitrogen and phosphorus removal performance. On day 10, the concentrations of total nitrogen (TN) and total phosphorus (TP) in the overlying water decreased to 2.70 and 0.36 mg/L, respectively, enabling this group to meet the Class I discharge standard of the Hubei Provincial Pollutant Discharge Standard for Aquaculture Tailwater. Specifically, tetracycline (TC), ibuprofen (IBU), and ofloxacin (OFX) were completely removed within 20 days, while erythromycin (ETM) achieved 100% removal within 30 days. High removal efficiencies were also observed for sulfamethoxazole (SMX), roxithromycin (RTM), thiamphenicol (TMN), and florfenicol (FF). Mechanistic analysis indicated that Maifanite mitigated the initial toxicity of high-concentration N, P, and antibiotics through adsorption, thereby supporting the growth of V. natans and its subsequent utilization of nitrogen and phosphorus for biomass accumulation. Furthermore, the synergy between Maifanite and V. natans improved the sediment oxidation-reduction potential (ORP), potentially regulating the community composition and relative abundance of functional bacteria targeting complex organic matter degradation, while effectively inhibiting the secondary release of internal pollutants. The system also showed desirable degradation performance for seven antibiotics and one typical pharmaceutical organic compound. Complete removal (100%) of TC, IBU, OFX (within 20 days), and ETM (within 30 days) was achieved. For SMX, RTM, TMN, and FF, the MFVS group also demonstrated high removal efficiency. These findings provide technical support and a theoretical basis for addressing combined pollution and sediment degradation in aquaculture environments, promoting green and sustainable farming practices.