In recent years, antibiotic residues are frequently detected worldwide that has posed a serious threat to drinking water and increased the risk of bacterial resistance. Sulfate radical (SO₄^•−)-based advanced oxidation has been regarded as an effective technology for refractory organic pollutants treatment. In this study, the degradation kinetics and mechanism of spiramycin (SPM) under thermally activated peroxydisulfate (PDS) oxidation process in aqueous solution were investigated for the first time. The results indicated that the degradation rate of SPM could be expressed as the kinetic rate equation -d[SPM]/dt=(2.96×10^-2 mM⁰ min^-1)[SPM]⁰[SPM]¹ within limited experimental conditions utilized here (i.e., 50 °C, pH 7, SPM 0.01-0.05 mM, and K₂S₂O₈ 1.0-2.72 mM). The apparent activation energy of 83.27 kJ·mol^-1 was calculated by Arrhenius equation. The SPM degradation rate decreased with the increase of pH value. The SO₄^•− and hydroxyl radical (•OH) were proved to be the dominant reactive species, but the contribution of SO₄^•− on the SPM oxidation gradually decreased with the increase of pH value. The presence of humic acid (HA) and inorganic anions negatively affected the SPM degradation. To investigate the possible reaction pathways of SPM under thermally activated PDS system, HPLC/ESI-QqQMS was employed to identify the intermediate products. In addition, the acute toxicity evaluated by Vibrio fischeri showed that the oxidation byproducts of SPM were not antibacterial. In summary, this study confirmed that the thermally activated PDS technology could be a promising, efficient, and environmental-friendly approach for removing SPM in aqueous solution.