In this study, alkaline-activated peroxodisulfate (PDS) coupled with anaerobic fermentation was employed to treat real oxytetracycline (OTC)-containing excess sludge. The results demonstrated that this system could effectively enhance the accumulation level of short-chain fatty acids (SCFAs) and degrade OTC therein. The experiment was conducted under the conditions of pH = 10 and PDS concentrations of 0.5/1.0/1.5/2.0/2.5/3.0 mmol/g VSS. When the PDS concentration was 1.5 mmol/g VSS, both the soluble chemical oxygen demand (SCOD) and SCFAs both hit their peak values. These maximums were 3208.39 mg/L and 730.74 mg COD/L, respectively. Two possible degradation pathways of OTC and a variety of small-molecule substances were deduced. The degradation mainly occurred through demethylation and decarbonylation. However, the OTC degradation capacity of this method was limited.