<p>Lycopene predominantly exists as an all-E isomer, but its Z-isomers are more abundant in the human body and have greater bioaccessibility and antioxidant activity than the all-E-isomer. This study aimed to develop an efficient isomerization method for Z-lycopene production and to fabricate Pickering emulsions loaded with high Z-lycopene content (PEZL) to enhance its stability and bioaccessibility, ultimately evaluating its potential effect against benign prostatic hyperplasia (BPH) in a mouse model. First, different methods to induce Z-isomerization of (all-E)-lycopene were investigated. Second, PEZL was fabricated and characterized for encapsulation efficiency, stability (under thermal, ionic, pH, and storage stress), in vitro digestion profile and bioaccessibility. Finally, its efficacy was assessed in a BPH mouse model by measuring the prostatic index (PI) and serum levels of acid phosphatase (ACP), testosterone (T), and dihydrotestosterone (DHT). This study developed an efficient production method for Z-lycopene by microwave heating at 560&#xa0;W for 5&#xa0;min with supplementation of garlic and onion at a 1:1 ratio. The total Z-lycopene content increased to approximately 71%, and the isomerization efficiency was higher than that with other isomerization methods. The PEZL prepared by zein-chitosan at the ratio of 1:1 demonstrated high encapsulation efficiency and robust stability. PEZL provided a 1.76-fold increase in the relative bioaccessibility compared to lycopene dissolved in perilla seed oil during simulated digestion in vitro. In the BPH model, PEZL administration significantly reduced the PI and serum levels of ACP, T, and DHT compared to the model group. The PEZL significantly improved the stability and bioaccessibility of Z-lycopene and shows promising preventive effects against BPH in vivo, providing a solid foundation for developing Z-lycopene-based functional foods or nutraceuticals for prostate health.</p>