Methotrexate (MTX) is a folic acid analog and has been used to treat a wide variety of malignant and non-malignant diseases. The wide use of these substances has led to the continuous discharge of the parent compound and its metabolites in wastewater. In conventional wastewater treatment plants, the removal or degradation of drugs is not complete. In order to study the MTX degradation by photolysis and photocatalysis processes, two reactors were used with TiO2as a catalyst and UV-C lamps as a radiation source. H2O2addition was also studied (absence and 3 mM/L), and different initial pHs (3.5, 7, and 9.5) were tested to define the best degradation parameters. Results were analyzed by means of ANOVA and the Tukey test. Results show that photolysis in acidic conditions with 3 mM of H2O2added is the best condition for MTX degradation in these reactors, with a kinetic constant of 0.028 min−1. According to the ANOVA test, all considered factors (process, pH, H2O2addition, and experimentation time) caused statistically significant differences in the MTX degradation results.