Psoralen is an endogenous compound with a linear furocoumarin structure, having a tricyclic structure in which coumarin and furan ring are present. The psoralen and its analogues are highly researched compounds in medicinal chemistry due to their various biological activities and use in photochemotherapy. It is known for its therapeutic activity in association with DNA interaction and photochemical reactions after exposure to ultraviolet A (UVA) light. Psoralen has the capability of forming a covalent adduct with the pyrimidine bases; however, further photochemical reactions may lead to formation of DNA interstrand cross-linking, affecting the replication and transcription of DNA. These reactions are responsible for the therapeutic action of psoralen but may also lead to phototoxicity and DNA damage. Modification in psoralen structure may be helpful in finding analogues with biological activity without phototoxicity. Changes in specific sites, such as C5 and C8, along with the modification of functional groups and heterocycles, have been proposed as methods for studying the properties of molecules. Molecular docking, physicochemical analysis, and ADMET prediction may help in screening potential compounds. Nevertheless, it is impossible to prove by computational models that the compounds are less phototoxic or capable of action without UVA.