Indiscriminate use of antibiotics to treat Staphylococcus aureus bovine mastitis may impair mammary glands immune function and develop bacterial resistance. Consequently, developing alternative remedies to treat mastitis is imperative. Current study evaluated plain multidrug resistant S. aureus vaccine (PMRSAV), Montanide oil adjuvanted multidrug resistant S. aureus vaccine (MMRSAV), and Aluminum hydroxide adjuvanted multidrug resistant S. aureus vaccine (AMRSAV) in lactating dairy cattle. Serum samples through IHA revealed that MMRSAV provoked maximum antibody titer at day 90 (274.4±0.41) whereas AMRSAV (147±0.46) and PMRSAV (78.8±0.44) produced highest antibody response at day 60. The cumulative mean serum IHA antibody titer was recorded highest for MMRSAV (148.4) than AMRSAV (78.4) and PMSAV (34.1). The peak milk whey antibody titer was seen at day 60 for PMRSAV (9±0.23) and AMRSAV (14.7±0.24) whereas it was observed highest at day 90 in MMRSAV (26.2±0.25). Somatic cell count (SSC: × 10⁵ mL^-1) observed decline trend in all the vaccinated cattle until day 90 for PMRSAV (1.449±0.219), day 120 for MMRSAV (1.201±0.097) and AMRSAV (1.327±0.104). During study period, the highest quarter-based incidence was observed in control group (25%) followed by PMRSAV (17.5%), AMRSAV (10%) and MMRSAV (5%) resulting incidence reduction (80%) for MMRSAV followed by AMRSAV (60%) and PMRSAV (30%). Post challenge lowest overall mean somatic cell count was recorded in group vaccinated with MMRSAV (2.323±0.46) followed by AMRSAV (3.006±0.43), PMRSAV (3.759±0.82) and unvaccinated control group D (7.798±1.11). The study concluded that MMRSAV is the most effective in preventing multidrug resistant S. aureus mastitis in dairy cattle.