To improve the efficiency of AD for tetracycline-containing wastewater, this study systematically investigated the effects of ZVI and PAC on pollutant removal, VFAs metabolism, biogas production, and sludge physicochemical characteristics. RSM was employed to optimize the co-dosing conditions of ZVI and PAC. The results demonstrated that ZVI and PAC could significantly facilitate COD degradation and TC removal, with the TC removal rate exceeding 90%. The optimal dosages for COD removal were 1000 mg/L ZVI and 2000 mg/L PAC with removal efficiency of 61.03% and 56.9%, respectively. Both additives effectively accelerated the catabolism of typical VFAs, thereby mitigating the accumulation of intermediate metabolites that may cause AD system instability. In terms of biogas production, 1000 mg/L ZVI and 2000 mg/L PAC enhanced methane yield by 55.9% and 35.0% compared to the control group, with ZVI exhibiting a more prominent enhancement effect. Mechanistic analysis revealed that ZVI and PAC reinforced the AD process through multiple synergistic pathways: enhancing the electrical conductivity of the AD system, facilitating DIET between functional microorganisms, and stimulating the secretion of EPS by anaerobic microbes. RSM optimization yielded the optimal co-dosing parameters: 1000 mg/L ZVI and 1200 mg/L PAC. Under these conditions, the methane yield was increased by 71.18% relative to the control group, and the model validation accuracy reached 97.94%. This study provides a viable technical strategy and theoretical basis for enhancing the efficiency of anaerobic treatment of tetracycline-containing wastewater.