<p>Lumpy Skin Disease (LSD), historically restricted to Africa, has in recent years exhibited a marked expansion into several Asian and European countries, resulting in substantial economic impacts on the global cattle industry. In August 2019, the first confirmed outbreak of LSD was documented in the Xinjiang region of China. In response to this emerging threat, our study established primary, basic, and working seed banks utilizing the LSDV/MZGD/2020 strain, which was isolated from Meizhou, Guangdong. These seed banks underwent rigorous validation via sterility assays and evaluation of proliferation characteristics. Optimal inactivation parameters for the virus were identified through systematic screening of different concentrations of β-propiolactone. Based on these optimized conditions, we developed two inactivated vaccine formulations: one employing the 201VG adjuvant and the other utilizing aluminum hydroxide adjuvant. Safety assessments demonstrated that both vaccines induced no significant irritation or adverse reactions in New Zealand rabbits and dairy cows, and that pathological examinations revealed no abnormal lesions. Immunogenicity analysis showed that the LSDV-201VG inactivated vaccine elicited robust and sustained serum neutralizing and specific antibody responses in cattle, with elevated antibody titers detected from weeks 4–5 and persisting for up to 8 weeks. In contrast, the vaccine formulated with aluminum hydroxide adjuvant generated relatively low antibody levels and failed to achieve requisite immunogenicity thresholds. Collectively, these results indicate that the LSDV-201VG inactivated vaccine exhibits high safety and immunogenic efficacy, providing a robust technical strategy for the prevention and control of LSD in China and Southeast Asia.</p>