Flavonoids are one of the most important metabolites in plants and they have important biological functions. Conventional extraction of this bioactive compounds has been used with organic solvents, but most of them are toxic and pollute the environment. As an alternative for organic solvents, natural deep eutectic solvents (NaDEs) have received more attention. The aim of this study was optimized and compare four different NaDEs for the extraction of flavonoids in orange peels. To optimize the extraction of flavonoids using NaDEs and magnetic stirring, a Response Surface Methodology (RSM) design was developed. Four different NaDEs systems with two components were obtained and examined in their corresponding molar ratios. Five levels were used for the optimization: solid-liquid ratio, extraction time and water content in NaDEs. Water content in NaDEs has significant impact on the extraction efficiency. The result showed the highest extraction was with Choline chloride: fructose (NaDEs-1) and 50% of NaDEs with a yield of 194.71± 4.58 mg/100g of dry matter. High water content can affect the hydrogen bonding interactions, which limit the solvent interaction with target components. However, without water was observed a yield reduction because the high viscosity of the NaDES. In all the cases the extraction with 85% of NaDEs extracted the minors yields of flavonoids. The optimum conditions of flavonoids extraction with NaDEs-1 were 50% of NaDEs, solid: liquid ratio of 1:25 and extraction time of 23 min. Based on literature the use of NaDEs for flavonoids extraction can improved the extraction yields by 7.0% in comparison with a traditional extraction with ethanol. The results demonstrate that the use of NaDEs is and efficient and ecofriendly alternative to extract flavonoids from orange peels and the variables studied had significant effects on measured responses.