Thionation of carbonyl groups of known dyes is a rapidly emerging strategy to propose an advance toward heavy-atom-free photosensitizers to be used in photodynamic therapy (PDT). The sulfur-for-oxygen replacement has recently proved to enhance the singlet oxygen quantum yield of some existing fluorophores and to shift the absorption band at longer wavelengths. Drawing inspiration from this challenging evidence, the effect of both sulfur- and selenium-for-oxygen replacement in the skeleton of the oxo-4-dimethylamino-1,8-naphthalimide molecule (DMN) has been analyzed by means of a DFT study. The thio- and seleno-derivatives (SDMN and SeDMN, respectively) have been shown to offer the possibility to access a multitude of ISC (intersystem crossing) pathways involved in the triplet deactivation mechanisms with a consequent enhancement of the singlet oxygen production, also arising from the change of orbital type involved in the radiationless 1nπ* → 3ππ* transitions. Moreover, the change in nature from a 1ππ* to a 1nπ* observed in the SeDMN has been revealed to be crucial to reach more clinically useful regions of the spectrum suggesting that the selenium-for-oxygen replacement can be proposed as a strategy to achieve more suitable PDT agents while proposing an advance toward heavy-atom-free PSs.