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<i>Streptococcus uberis</i> mastitis in cattle infects mammary epithelial cells. Although oxidative responses often remove intracellular microbes, <i>S. uberis</i> survives, but the mechanisms are not well understood. Herein, we aimed to elucidate antioxidative mechanisms during pathogenesis of <i>S. uberis</i> after isolation from clinical bovine mastitis milk samples. <i>S. uberis</i>’s in vitro pathomorphology, oxidative stress biological activities, transcription of antioxidative factors, inflammatory response cytokines, autophagosome and autophagy functions were evaluated, and in vivo <i>S. uberis</i> was injected into the fourth mammary gland nipple of each mouse to assess the infectiousness of <i>S. uberis</i> potential molecular mechanisms. The results showed that infection with <i>S. uberis</i> induced early oxidative stress and increased reactive oxygen species (ROS). However, over time, ROS concentrations decreased due to increased antioxidative activity, including total superoxide dismutase (T-SOD) and malondialdehyde (MDA) enzymes, plus transcription of antioxidative factors (Sirt1, Keap1, Nrf2, HO-1). Treatment with a ROS scavenger (N-acetyl cysteine, NAC) before infection with <i>S. uberis</i> reduced antioxidative responses and the inflammatory response, including the cytokines IL-6 and TNF-α, and the formation of the Atg5-LC3II/LC3I autophagosome. Synthesis of antioxidants determined autophagy functions, with Sirt1/Nrf2 activating autophagy in the presence of <i>S. uberis</i>. This study demonstrated the evasive mechanisms of <i>S. uberis</i> in mastitis, including suppressing inflammatory and ROS defenses by stimulating antioxidative pathways.