The present work investigates the photocatalytic degradation efficiency of biorecalcitrant macrolide antibiotics in a circulating tubular photoreactor. As target pollutants, spiramycin (SPM) and tylosin (TYL) were considered in this study. The photoreactor leads to the use of an immobilized titanium dioxide on non-woven paper under artificial UV-lamp irradiation. Maximum removal efficiency was achieved at the optimum conditions of natural pH, low pollutant concentration and a 0.35 L min−1 flow rate. A Langmuir–Hinshelwood model was used to fit experimental results and the model constants were determined. Moreover, the total organic carbon analysis reveals that SPM and TYL mineralization is not complete. In addition, the study of the residence time distribution allowed us to investigate the flow regime of the reactor. Electrical energy consumption for photocatalytic degradation of macrolides using circulating TiO2-coated paper photoreactor was lower compared with some reported photoreactors used for the elimination of pharmaceutic compounds. A repetitive reuse of the immobilized catalyst was also studied in order to check its photoactivity performance.