In the present study, Passiflora foetida extracts characterized by different polarities were studied for their phytochemical profile, enzyme inhibitory, and antioxidant potentials. In silico, in vitro and ex vivo studies were also carried out on methanol and water extracts for predicting pharmacokinetics and pharmacodynamics. In this regard, neuronal HypoE22 cells, isolated mouse skin tissues, and pathogen dermatophytes strains were exposed to extracts. Emphasis was given to the preventing effects induced by the extracts on hydrogen peroxide-induced alterations of prostaglandin E2 (PGE2), l-dopa, and serotonin. Chemical analysis revealed the presence of similar compounds in infusion and methanolic extracts. The ex vivo studies also showed protective skin properties by P. foetida water and methanol extracts, as evidenced by the decrease of hydrogen peroxide-induced PGE2 level. Additionally, the blunting effects on hydrogen peroxide-induced l-dopa levels are consistent with the anti-tyrosinase effect exerted by both extracts. In silico studies demonstrated the affinity of extracts’ phytochemicals, namely apigenin, chrysoeriol, loliolide, luteolin, quercetin, and vitexin, towards cyclo-oxygenase-2 and tyrosinase. Finally, microbiological tests demonstrated the efficacy of P. foetida methanol and water extracts as anti-mycotic agents against Trichophyton and Arthroderma species, involved in skin inflammation. Hence, P. foetida L. extracts could represent potential sources of pharmaceuticals and nutraceuticals.