The current work investigates the removal of two hazardous macrolide molecules, spiramycin and tylosin, by photodegradation under external UV-light irradiation conditions in a slurry photoreactor using titanium dioxide as a catalyst. The kinetics of degradation and effects of main process parameters such as catalyst dosage, initial macrolide concentration, light intensity and stirring rate on the degradation rate of pollutants have been examined in detail in order to obtain the optimum operational conditions. It was found that the process followed a pseudo first-order kinetics according to the Langmuir–Hinshelwood model. The optimum conditions for the degradation of spiramycin and tylosin were low compound concentration, 1 g L−1 of catalyst dosage, 100 W m−2 light intensity and 560 rpm stirring rate. Then, a maximum removal (more than 90%) was obtained after 300 min of irradiation time. Furthermore, results show that the selection of optimized operational parameters leads to satisfactory total organic carbon removal rate (up to 51%) and biochemical oxygen demand to chemical oxygen demand ratio (∼1) confirming the good potential of this technique to remove complex macrolides from aqueous solutions.