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In the present, whitening products are most popular in the cosmetics market, and nanoemulsions are effective drug delivery systems through the skin. The objective of this study was to investigate multiple nanoemulsion formulations for lightning skin effects. The method of this study was the selection of active compounds based on synergistic tyrosinase inhibition activity, formulation preparation by low and high energy methods, physicochemical property determination, stability test, cell toxicity, and anti-melanogenesis in cell culture. From the results, it was found that tyrosinase inhibition with substrate l-tyrosine from the mixture of curcumin and alpha-arbutin gave the highest activity with an IC 50 of 63.58 ± 4.99 μM, showed a synergistic effect at a CI value of 0.99, and selected these compounds to develop formulations by the low energy method. However, the most formulations prepared by this method were unstable and phase separated, while the high energy method gave the most formulations with good properties, which were selected for further investigation. The best formulation was 2DS which showed internal droplet morphology in the range of nanometers under a TEM microscope. For 3 months stability test, the formulations had no phase separation and gave the slightly changed values of particle size, polydispersity index (PDI), zeta potentials, and pH values. In addition, multiple nanoemulsions also enhanced the stability of active compounds, with the highest percentage of remaining content of curcumin and arbutin at 94.69 and 90.45 %, respectively at 4 °C for 3 months. In a cell culture test on B 16 F 10 , 2DS at 0.05 g/ml gave no cell cytotoxicity and anti-melanogenesis at 57.75 ± 5.74 %, the same potency as kojic acid at a concentration of 20 μg/ml. Therefore, this study will be useful to prepare multiple nanoemulsions for further development into novel health care products., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)