Nebivolol (NEB) is widely used for the treatment of hypertension and chronic heart failure and has become an ubiquitous emerging organic pollutant. It has been shown to undergo direct photolysis, but the role of DOM in its degradation kinetics and mechanism is not well understood. In this study, we studied the photochemical behavior of NEB in the presence of seawater DOM (SW-DOM) and freshwater DOM (SRNOM) under simulated sunlight irradiation. SW-DOM had a promotion effect on NEB photodegradation, whereas SRNOM retarded its photolytic transformation. After eliminating the influence of light screening, we found that the indirect photodegradation rate of NEB in the presence of SRNOM was lower than that in the presence of SW-DOM. Results show that the indirect photodegradation pathway occurred by reaction with triplet-excited DOM (3DOM*). The second-order rate constants for 3SW-DOM* and 3SRNOM* reaction with NEB are 3.7 × 109 M-1 s-1 and 3.7 × 108 M-1 s-1, respectively. The electron donating capacity of SRNOM is higher than that of SW-DOM, indicating that SRNOM may contain more activated phenolic moieties. SRNOM may thus have higher antioxidant activity, leading a higher inhibitory effect on NEB photodegradation. A total of six degradation products were identified in the absence and presence of DOM by HPLC-ESI-MS/MS. The substitution of F by OH-groups and further oxidation a OH-group in the lateral chain to a ketone, and cleavage of N-C bond by the attack of 3DOM* are here proposed as the main degradation pathways.