Background: Traditionally, Foeniculum vulgare (fennel seeds) has been used for its antimicrobial, analgesic, antipyretic, antiflatulence, antispasmodic, and antiandrogenic activities. Materials and Methods: In the present study, the protective effect of flavonoids from fennel seeds was investigated against ultraviolet (UV)-B radiation-induced cell damage and oxidative stress in human dermal fibroblast (HDF) cells. Results: Flavonoid-enriched fraction (FEF) of fennel seeds showed high flavonoid content and antioxidant potential as well as the presence of a marker compound rutin. Pretreatment of HDF cells with the FEF (15-45 µg/ml) significantly protected against UV-B-induced cytotoxicity, endogenous enzymatic antioxidant depletion, oxidative DNA damage, intracellular reactive oxygen species generation, and apoptotic morphological changes. Conclusion: The current study proved for the first time that the FEF of fennel seeds reduced oxidative stress through the nuclear factor E2-related factor 2-antioxidant response elements pathway. Flavonoids from fennel seeds have a potential as UV-B protectants and can be explored against diseases, in which oxidative stress is closely implicated. [ABSTRACT FROM AUTHOR]