In the present study, cytotoxic (apoptotic and necrotic), antioxidant, prooxidant, genotoxic, and apoptosis- related genes expression modulatory effects of physodic acid (PA) isolated from Pseudevernia furfuracea on cancerous (HepG2) and healthy (THLE2) human liver cells were evaluated. Cytotoxic effects PA obtained from P. furfuracea on HepG2 and THLE2 cells were tested via MTT and LDH analyses. In order to determine genotoxic effect of PA, 8-OH-dG levels in the cells were measured. In addition, apoptotic or necrotic effects of PA on the hepatic cells were determined by qRT-PCR analysis. Cytotoxicity analyses revealed the cytotoxic effect of PA on HepG2 cells, which is much higher than THLE2 cells. Gene expression studies demonstrated the apoptotic effects of PA on HepG2 cells through both extrinsic and intrinsic pathways. PA increased the antioxidant capacity of THLE2 cells with increasing concentrations, which describes its antioxidant power. Additionally, none of the tested levels of PA caused oxidative DNA damage on THLE2 cells, but its high concentration increased genetic damages on HepG2. Taken together, P. furfuracea lichen and its metabolite, PA, would be a promising alternative for complementary treatments against liver cancer. Keywords: 8-Hydroxy-20-deoxyguanosine; lactate dehydrogenase; lichen; total antioxidant capacity; total oxidative stress.