Objectives: The study was aimed to compare the effects of seven different kinds of ginsenosides and total saponins on melasma and to explore their related mechanisms. Materials and Methods: The inhibitory rate of ginsenosides on tyrosinase (TYR) activity was measured in vitro. The skin cream comprising different kinds of ginsenosides was prepared and the melasma mice model was established. After successful modeling, different skin creams were applied to the backside of mice for 30 days and these mice were separated into 11 groups. Afterward, the melanocytes and melanin in the epidermal cells were analyzed under the microscope. Finally, the activity of superoxide dismutase (SOD), TYR and the content of malondialdehyde (MDA) in melasma mice were determined by different assay kits. Results: The outcomes of in vitro experiment showed that ginsenosides could affect TYR activity with different concentrations. In the melasma mice model, ginsenosides and total saponins inhibited the growth of melanocytes and the synthesis of melanin. Furthermore, with the increasing use of skin cream comprising ginsenosides and total saponins, the activity of SOD showed an increase trend, while MDA content and TYR activity exhibited a decrease trend. Thirty (30) days of treatment with ginsenosides (except for Rg1 and Rg2) and total saponins significantly increased the SOD activity and decreased the MDA and TYR levels compared with those in melasma mice without treatment (P < 0.05). Conclusion: Skin cream comprising ginsenosides Rb1, Rc, Rd, and Re could employ better protective roles in melasma by suppressing oxidative stress and inhibiting the synthesis of melanin.