The presence of antibiotics, such as sulfadiazine (SDZ), in the aquatic environment contributes to the generation of antimicrobial resistance, which is a matter of great concern. Photolysis is known to be a major degradation pathway for SDZ in surface waters. Therefore, influencing factors affecting SDZ photodegradation in different aquatic environments were here evaluated in order to have a better knowledge about its persistence in the environment. Photodegradation of SDZ was found to be more efficient at higher pH (t1/2 = 6.76 h, at pH = 7.3; t1/2 = 12.2 h, at pH = 6.3), in the presence of humic substances (HS) (t1/2 between 1.76 and 2.42 h), as well as in the presence of NaCl (t1/2 = 1.00 h) or synthetic sea salts (t1/2 = 0.78 h). Using ˙OH and 1O2 scavengers, it was possible to infer that direct photolysis was the main pathway for SDZ photodegradation in ultrapure water. Furthermore, results under N2 purging confirmed that 1O2 was not relevant in the phototransformation of SDZ. Then, the referred observations were used for the interpretation of results obtained in environmental matrices, namely the final effluent of a sewage treatment plant (STPF), fresh and brackish water (t1/2 between 2.3 and 3.48 h), in which SDZ photodegradation was found to be much faster than in ultrapure water (t1/2 = 6.76 h). •Sulfadiazine (SDZ) photodegradation was found to be more efficient at higher pH.•Dissolved organic matter resulted in an increase of SDZ photodegradation.•Salinity and reactive halogen species caused an increase in SDZ photodegradation.•Direct photolysis was the main path for SDZ photodegradation in ultrapure water.•t½ decreased from 6.76 h in ultrapure water to 2.3–3.48 h in environmental samples.