The frequent detection of artificial sweeteners (ASs) in wastewater and surface water gives rise to concerns about their removal, Acesulfame (ACE) and sucralose (SUC) are two ASs that are difficult to remove. The ultraviolet/persulfate (UV/PS) advanced oxidation technology (AOT) is being considered as an effective process for the degradation of micropollutants in wastewater. However, the study of the degradation of ASs in real wastewater by the UV/PS is minimal. This study investigated the kinetics and modeling of ACE and SUC degradation in wastewater by the UV/PS process. Both ACE and SUC could be degraded effectively using this process. The degradation of ACE was mainly attributed to UV photolysis (51%), HO∙ (26%) and SO4∙- (16%), while that of SUC was mainly attributed to HO∙ (68%) and SO4∙- (27%). The second-order rate constants of ASs with SO4∙- were significantly lower than that with HO∙. Three major transformation products (TPs) of ACE and four major TPs of SUC were identified. Additionally, the effects and mechanisms of the water matrices, such as HCO3-, Cl-, NO3- and natural organic matter (NOM), on ASs degradation were investigated through response surface methodology (RSM). NOM and Cl- significantly inhibited the degradation of ACE in the UV/PS system, whereas NOM and HCO3- played a main inhibition role on the degradation of SUC. A water matrices parameter model for predicting ASs degradation in real wastewater was established by RSM for the first time, and the removal of ACE and SUC was well predicted by the model.