Among the different antibiotics, tetracycline hydrochloride (TCH) is one of the most commonly used. In this study, the activated sodium persulfate (SPS) process induced by microwave (MW) energy was used to treat TCH. The effect of different operational parameters of MW/SPS-treated TCH, such as SPS concentration, TCH concentration, initial pH, and MW power, was investigated. The concentration changes of TCH were determined using a spectrophotometer. The results of radical scavenger experiments indicated that the sulfate radical () was stronger than the hydroxyl radical (·OH). On the basis of high performance liquid chromatography–mass spectrometry (HPLC–MS) analysis, a possible degradation pathway of TCH was proposed. This research indicates that the MW/SPS system is a promising prospect for the treatment of TCH.