Lumpy skin disease (LSD) is an infectious disease affecting large ruminants, caused by the lumpy skin disease virus (LSDV). It is characterized by symptoms such as hyperthermia, emaciation, lymphadenopathy, and skin nodules. Pregnant animals affected by LSD often experience abortions and may develop infertility syndrome, while affected males can become sterile. A live attenuated goat pox virus vaccine (GTPV) was administered to various groups of crossbred buffaloes. After vaccination, blood samples were collected from each group to analyze post-vaccination antibody titers. Additionally, vaccinated calves and buffaloes were monitored for growth, body temperature, blood profile, milk production and quality, and reproductive parameters. The study revealed an increase in antibody titer in the weeks following vaccination, with sustained levels for over 150 days before declining by 300 days. During the 7-day observational phase, the vaccinated calves and replacement heifers exhibited significant growth. There were no notable changes in body temperature or milk production in lactating buffaloes within 7 days post-vaccination. However, the buffalo category affected all blood profile indicators significantly (P <
0.05) except for MCHC (P >
0.05) after LSD vaccination. An interaction (P <
0.05) was observed between buffalo categories and days post-exposure for RBCs, HGB, HCT, and MCV values in vaccinated buffaloes. Reproductive parameters, including ovarian resumption, uterine involution rates, and synchronization rate, remained similar in both vaccinated and unvaccinated buffaloes. Overall, the use of the attenuated GTPV vaccine induces a considerable antibody titer without influencing general health or productive parameters, making it a safe and economical method for preventing LSD in buffaloes.