Abstract: To enhance the stability and antioxidant activity of proanthocyanidin, nanoliposomes of proanthocyanidin were prepared from soybean lecithin and cholesterol using a synergistic reverse evaporation-ultrasound-microwave technique. Single-factor experiments were conducted to investigate the effects of proanthocyanidin concentration, lecithin-to-cholesterol mass ratio, rotary evaporation temperature, ultrasound power, microwave power, and microwave time on the encapsulation efficiency, DPPH free radical scavenging activity, particle size, polydispersity index (PDI), and ζ-potential. Then Plackett-Burman and response surface experiment were used to optimize the preparation processing. The structure, stability, and in vitro antioxidant activity of the proanthocyanidin nanoliposomes were also evaluated. The results showed that the optimal preparation conditions were proanthocyanidin concentration of 0.6 mg·mL⁻¹, lecithin-to-cholesterol mass ratio of 7:1, rotary evaporation temperature of 45 ℃, ultrasound power of 180 W, microwave power of 200 W, and microwave time of 83 seconds. Under these conditions, the encapsulation efficiency was 94.84%, the DPPH radical scavenging rate was 69.07%, the particle size was 182.96 nm, the PDI was 0.247, and the ζ-potential was −18.43 mV. Transmission electron microscopy revealed that the proanthocyanidin nanoliposomes exhibited single-layer, multi-layer, and multi-vesicular structures. The proanthocyanidin nanoliposomes should be stored in the dark below 20 ℃, metal ions caused less degradation on proanthocyanidin nanoliposomes than on proanthocyanidin solution. The highest preservation of proanthocyanidin in the nanoliposomes occurred at pH8.0. The in vitro release rate of proanthocyanidin from the nanoliposomes (77.911%) was lower than that of the proanthocyanidin solution (92.405%), indicating a controlled release effect. The lower IC₅₀ values for scavenging DPPH and ABTS⁺ radicals by proanthocyanidin nanoliposomes compared to free proanthocyanidin solution indicated that liposome encapsulation improved the antioxidant activity of proanthocyanidin. The study demonstrates that the reverse evaporation-ultrasonic-microwave synergistic technique effectively enhances the encapsulation efficiency and antioxidant activity of proanthocyanidin in nanoliposomes.