To explore the multivariate effects of seawater constituents on the photochemical transformation of antibiotics, response surface methodology (RSM) was employed to investigate the multivariate effects of water constituents (i.e., dissolved organic matter (DOM), HCO₃^-, NO₃^-, and Cl^-) on the photodegradation of sulfapyridine as a representative of sulfonamide antibiotics (SAs). The results showed that at p < 0.05significance level, both DOM and HCO₃^--NO₃^- interaction significantly impacted the photogradation of sulfapyridine. HCO₃^- can quench ·OH that is photo-induced formation by NO₃^- resulting in the inhibitive effect of HCO₃^--NO₃^- interaction. Radical scavenging experiments unveiled that the enhancive effect of DOM on the photodegradation of sulfapyridine was mainly attributed to triplet-excited DOM (³DOM^*). Steady experiments conducted by DOM proxies (aromatic ketones) demonstrated that the relationship between logarithms of photolytic rate constants of sulfapyridine and the oxidation potentials of triplet-excited DOM proxies was positive correlated well. Further experiments found that the triplet-excited reactivity of SAs was determined by their energy gaps of HOMO-LUMO.