Bovine mastitis caused by Streptococcus agalactiae (S. agalactiae) has resulted in substantial economic loss to the animal husbandry industry; however, the associated molecular mechanism remains unclear and the role of TNFRSF21 in the inflammatory response caused by S. agalactiae is unknown. In this study, we focused on bacterial isolation and identification, histological observations, and provide the first report of the association between TNFRSF21 and pyroptosis. The results showed that S. agalactiae-induced inflammation can cause increasing damage of the tissue and pyroptosis ratio, significantly increased the level of inflammatory cytokine production (e.g., NLRP3, caspase-1, and IL-1β), and upregulate TNFRSF21 following S. agalactiae infection in a time-dependent manner. In conclusion, these findings indicated that it may fight against the inflammatory response induced by S. agalactiae by inhibiting TNFRSF21 expression and reducing NLRP3 inflammasome pathway-mediated inflammatory necrosis.