Polygodial is a bioactive compound that is present in an ancient native plant known as "horopito" (Pseudowintera colorata) in New Zealand, and it possesses antifungal, antibacterial, antifeedant, insecticidal, and antithelmintic properties. In this work, an approach for polygodial extraction using deep eutectic solvents (DESs) is presented. Two newly prepared DESs based on 1-dodecanol and polyethylene glycol were found to be comparable with ethanol in their polygodial extractability. However, they exposed a superior ability to protect polygodial from degradation and also a better solvent reusability for extraction of polygodial as compared to ethanol. The Box-Behnken design (BBD) in combination with response surface methodology (RSM) was used to design the experiment and optimization of polygodial extraction using the dodecanol-based DES. The optimal condition was acquired at 47.13 °C, for 1.03 h, and 5.01% w/v biomass, where 12.35 ± 0.05 mg of polygodial/g of dried horopito leaf was extracted.