The present investigation has focused on developing an eco-friendly method to extract bioactive compounds from orange peel using natural deep eutectic solvents (NADES). NADES-II composed of choline chloride (ChCl) and ethylene glycol (1:2) and 50% water shows the maximal extraction yield with higher antioxidant activity in terms of DPPH and ABTS scavenging activity with a high total phenolic content (TPC) and total flavonoid content (TFC). The microwave-assisted extraction (MAE) process was optimized using response surface methodology (RSM) and an artificial neural network (ANN). ANN showed a higher value of R ² and lower values of other statistical parameters when compared to RSM. The ideal extraction conditions were optimized as a 13 min rising time, 52 °C temperature, a 21 min holding time, and a 20 mL/g liquid-to-solid ratio. MAE was compared with the conventional heating-stirring extraction (HSE) method using the NADES-II solvent under optimum conditions. The results show that higher extraction yield and antioxidant capacities (DPPH and ABTS), TPC, and TFC can be obtained from orange peel using the MAE process compared to the HSE process. Overall, this study shows an optimiztic approach for the extraction of bioactive compounds from an orange peel using eco-friendly solvents and microwave technology. It also highlights the potential of this approach for valorizing orange peel waste.