Citalopram (CIT) is a commonly prescribed medication for depression. However, the photodegradation mechanism of CIT has not yet been fully analyzed. Therefore, the photodegradation process of CIT in water is studied by density functional theory and time-dependent density functional theory. The calculated results show that during the indirect photodegradation process, the indirect photodegradation of CIT with ·OH occurs via OH-addition and F-substitution. The minimum activation energy of C10 site was 0.4 kcal/mol. All OH-addition and F-substitution reactions are exothermic. The reaction of1O2with CIT includes the substitution of1O2for F and an addition reaction at the C14 site. TheEavalue of this process is 1.7 kcal/mol, which is the lowest activation energy required for the reaction of1O2with CIT. C–C/C–N/C–F cleavage is involved in the direct photodegradation process. In the direct photodegradation of CIT, the activation energy of the C7-C16 cleavage reaction was the lowest, which was 12.5 kcal/mol. Analysis of theEavalues found that OH-addition and F-substitution, the substitution of1O2for F and addition at the C14 site, as well as the cleavage reactions of C6–F/C7–C16/C17–C18/C18–N/C19–N/C20–N are the main pathways of photodegradation of CIT.