Panax notoginseng has gained attention for its potential efficacy and mechanisms in skin whitening and spot removal. In this study, we investigated the effects of pre-columnar saponins and polysaccharides from the roots, as well as pre-columnar saponins and flavonoids from the stems and leaves, in the prevention and treatment of melasma. We further explored their molecular mechanisms, focusing on the Nrf2/ARE signaling pathway. Inhibition of tyrosinase (TYR) activity and antioxidant activity assays showed that all four active compounds could effectively inhibit TYR activity and enhance antioxidant capacity in vitro and in vivo. In addition, the mechanism of action, RT-qPCR, Western blot and immunofluorescence assays showed that they were involved in the Nrf2/ARE pathway, up-regulating the expression of Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2) and Heme Oxygenase 1 (HO-1) mRNAs, while down-regulating Kelch-like ECH-associated protein 1 (Keap1). Overall, these four compounds from P. notoginseng exhibited significant TYR inhibitory and antioxidant effects, ameliorating melasma in mice via the Nrf2/ARE pathway. These findings suggest that they may serve as promising therapeutic candidates for melasma treatment.