In order to investigate the effect of compound antibiotics on anaerobic digestion of chicken manure, the inhibitory effect of three different combinations of oxytetracycline (OTC), sulfamethoxazole (SMZ), and enrofloxacin (ENR) on anaerobic digestion of chicken manure was studied by the sequencing batch method. Under the condition of adding three different combinations of antibiotics, the experiment was run for 50 days. The concentrations of soluble chemical oxygen demand (SCOD), total ammonia nitrogen (TAN), VFAs, and methane production in the reactor were measured, and the microbial diversity affecting the stability of the system was analyzed. The results showed that OTC and SMZ inhibited methane production, while SMZ and ENR promoted methane production, and the cumulative methane production was R4>R3>R1>R2. After the 25th day, the SCOD concentration in the R2 and R4 groups decreased, which was due to the existence of SMZ and ENR promoting the degradation of SCOD. TAN concentrations in the four groups were kept between 1,190 and 2,100 mg/L. The results of 16S rRNA sequencing showed that the mixed antibiotics had different effects on the bacterial community, which was mainly composed of Firmicutes, Bacteroidota, unidentified bacteria, Cloacimonadota, Proteobacteria, and Spirochaetota. Bacteroidota was superior in the whole reaction process under the influence of OTC and SMZ because it stimulated the microbial flora and made its activity higher. The study provides relevant data for the proper management of livestock manure.