The study concerns the photodegradation of the antidepressant escitalopram (ESC), the S-enantiomer of the citalopram raceme, both in ultrapure and surface water, considering the contribution of indirect photolysis through the presence of nitrate and bicarbonate. The effect of nitrate and bicarbonate concentrations was investigated by full factorial design, and only the nitrate concentration resulted in having a significant effect on the degradation. The kinetics of ESC photodegradation is the pseudo-first-order (half-life = 62.4 h in ultrapure water and 48.4 h in lake water). The generation of transformation products (TPs) was monitored through a developed and validated HPLC-MS/MS method. Fourteen TPs were identified in ultrapure water (one of them, at m/z 261, for the first time) and other two TPs at m/z 327 (found for the first time in this study) were identified only in presence of a nitrate. Several TPs were the same as those formed during the photodegradation of citalopram. The photodegradation pathway of ESC and its mechanism of degradation in water is proposed. The method was applied successfully to the analyses of surface water samples, in which a few dozen of ng L−1 of ESC was determined together with the presence of TP2, TP5 and TP12. Finally, a preliminary in silico evaluation of the toxicological profile and environmental behavior of TPs by computational models was carried out; two TPs (TP4 and TP10) were identified as of potential concern, as they were predicted mutagenic by Ames test model.