Display omitted •The degradation of SMP in water was accomplished by UV-activated persulfate.•The second-order rate constants of SMP with SO4– and OH were derived.•Degradation pathways based on transformation products analysis were proposed.•Impacts of UV/PS treatment on DBP formation during post-chlorination were evaluated. The kinetics and mechanisms of the degradation of sulfamethoxypyridazine (SMP) by an ultraviolet-activated persulfate (UV/PS) advanced oxidation process (AOP) and the formation of disinfection byproducts (DBPs) during subsequent chlorination were investigated in this study. The UV/PS process can significantly remove SMP through pseudo-first-order reaction kinetics. In a competitive kinetic experiment, the second-order rate constant of SMP with sulfate radical was determined to be 2.73 × 1010 M−1 s−1, while that with hydroxyl radical was 2.22 × 1010 M−1 s−1. Six major transformation products in SMP degradation were recognized by LC/MS/MS analysis. It was assumed that the degradation pathway of SMP involves the hydroxylation of the aromatic ring, cleavage of the sulfonamide bond, oxidation of the aniline moiety and elimination of SO2. The impacts of persulfate dose, pH, anions (HCO3–, SO42−, and Br−) and humic acid (HA) concentration on SMP degradation efficiency and DBP formation during subsequent chlorination were also examined. SMP degradation was accelerated with increasing persulfate dose, HCO3– and Br- concentration as well as decreasing pH and HA concentration. However, the amount of chloroform (CF) formed was reduced under a higher persulfate dosage and lower pH. In contrast, the amount of dichloroacetonitrile (DCAN) formed was enhanced under a higher persulfate dose and lower pH. Adding HA also increased the formation of both CF and DCAN. While, both HCO3– and SO42– had little effects on the formation of CF and DCAN. The presence of Br– had no significant effects on the bromine incorporation factors (BIFs) of trihalomethanes (THMs) and dihaloacetonitriles (DHANs). Raw water experiments showed that the UV/PS process could destroy SMP in natural water as well as control the formation of DBPs.