Although photochemical transformation is a major degradation pathway for antibiotics in surface freshwaters, the photodegradation of antibiotics from freshwaters downstream into seawater is largely unknown. Herein, sulfadiazine was adopted as a representative antibiotic to probe the alteration of photolytic kinetics along freshwater to seawater sampled from Qinzhou Bay, China. The results showed that the photodegradation rate constants of sulfadiazine significantly increased in estuarine waters along freshwaters to seawaters. Experiments in synthetic water samples with isolated local dissolved organic matter (IL-DOM) indicated that the increased photodegradation of sulfadiazine is attributed to the integrative effect of both IL-DOM and halide ions. Radical quenching experiments with tert-butanol (quenching of ·OH) and isopropanol (quenching of both ·OH and reactive halogen species, RHS) demonstrated that RHS are largely responsible for the halide-specific enhancement in the photodegradation of sulfadiazine, rather than other reactive species, such as triplet-excited IL-DOM and ·OH. However, triplet-excited IL-DOM was involved in the production of RHS by the oxidation of halide ions by the triplet-excited states. Experiments conducted with DOM analogues verified DOM-sensitized RHS formation, and the degradation induced by RHS is positively correlated with the triplet-excited reduction potentials of DOM analogues. These findings are helpful in deeply understanding the transformation of antibiotics, and demonstrate the importance of RHS-induced degradation in antibiotics fate models in estuarine water systems.