This study evaluated the whitening effects of flavonoids extracted from Petasites japonicus root (PJR) using in vitro and cell-based assays to assess their cytoprotective, enzyme-inhibitory, and melanogenesis-suppressive activities. PJR flavonoids (30~60 μg/mL) showed no cytotoxicity and slightly enhanced cell proliferation at 40 μg/mL. Sodium nitroprusside (0.3 mM) decreased cell viability to 31%, whereas PJR restored it to 68.3%. PJR exhibited dose-dependent α-glucosidase inhibition (20.3~63.2%), indicating its potential to modulate skin glycation and pigmentation. In the malondialdehyde inhibition assay, PJR reduced lipid peroxidation by 35~60%, further supporting its antioxidative capacity. 3,4-Dihydroxyphenylalanine oxidation was suppressed by up to 68.9%, indicating reduced formation of the melanin precursor. The tyrosinase activity decreased from 145% to 86.9% and melanin synthesis was reduced from 105% to 66.9% in a concentration-dependent manner, showing a whitening efficacy comparable to that of arbutin. Overall, these findings indicate that PJR flavonoids possess antioxidative, antiglycation, and antimelanogenic properties and offer strong potential as safe multifunctional ingredients for functional cosmetic and food applications.