The present study investigated the reactivity and oxidation mechanisms of salbutamol (SAL) and terbutaline (TBL), two typical β2-adrenoceptor agonists, towards sulfate radical (SO4−) by using photo-activated persulfate (PS). The reaction pathways and mechanisms were proposed based on products identification using high resolution HPLC-ESI-MS, laser flash photolysis (LFP) and molecular orbital calculations. The results indicated that SO4− was the dominant reactive species in the UV/PS process. The second-order rate constants of sulfate radical reaction with SAL and TBL were measured as (3.7 ± 0.3) × 109 and (4.2 ± 0.3) × 109 M−1 s−1 by LFP, respectively. For both SAL and TBL, phenoxyl radicals were found to play key roles in the orientation of the primary pathways. For SAL, a benzophenone derivative was generated by oxidation of the phenoxyl radical. However, in the case of TBL, the transformation of the phenoxyl radical into benzoquinone was impossible. Instead, the addition of OSO3H on the aromatic ring was the major pathway. The same reactivity pattern was observed in the case of TBL structural analogs resorcinol and 3,5-dihydroxybenzyl alcohol. Our results revealed that basic conditions inhibited the decomposition of SAL and TBL, while, increasing PS dose enhanced the degradation. The present work could help for a better understanding of the difference in oxidation reactivity of substituted phenols widely present in natural waters.