In present work, the degradation of antibiotic and inactivation of antibiotic resistance genes (ARGs) in cephalosporin C fermentation (CEPF) residues were performed using ionizing radiation, ozonation and thermal treatment. The results showed that the three treatment methods could degrade cephalosporin C effectively, with the removal efficiency of 85.5% for radiation at dose of 100 kGy, 79.9% for ozonation at dosage of 5.2 g O/L, and 71.9% and 87.3% for thermal treatment at 60 °C and 90 °C for 4 h. The cephalosporin resistance gene tolC was detected in the raw CEPF residues, and its abundance was decrease 74.2% by radiation, 64.6% by ozonation and 26.9%-37.1% by thermal treatment respectively. The presence of protein, glucose and acetate in the CEPF residues had inhibitive influence on the degradation of cephalosporin C by ionizing radiation, and the effect was more significant when the antibiotic concentration was lower. The total content of COD, polysaccharides and protein changed slightly after radiation and thermal treatment, while they were decreased greatly by ozonation. The primary techno-economic analysis showed that the operational cost of ionizing radiation by electron beam at 50 kGy ($5.2/m) was comparable to thermal treatment ($4.3-7.9/m), which was more economical than ozonation ($14.6/m).