Mastitis is a common disease that affects women during lactation, posing a threat to the health of both mothers and infants. Recent studies have shown that insufficient nutrient intake increase the risk of mastitis. Phlorizin (PHZ) is one of the nutrients present in apples. This study uses Lipopolysaccharide (LPS)-induced mastitis mice and LPS+ATP-stimulated mouse mammary epithelial cells (mMECs) as research objects to explore the effect and mechanism of PHZ on mastitis. Different to in vitro beliefs, our findings demonstrated that PHZ significantly reduced inflammation and protected the blood–milk barrier (BMB) in vivo. Additionally, we observed that oral administration of PHZ regulated the intestinal flora and exhibited prebiotic functions. However, the anti-inflammatory effect of PHZ was not solely dependent on the intestinal flora, as antibiotic disruption of the intestinal flora does not completely abolish the improvement of mastitis by PHZ. Further mechanistic research revealed that the anti-inflammatory properties of PHZ were attributed to its metabolism into phloretin (PHT). Moreover, our results demonstrated that PHT reduced inflammation and protected the BMB by promoting autophagy to prevent the pyroptosis of mMECs. This study provides a theoretical basis for reducing inflammation in lactating women by consuming fruits, such as apples, that contain PHZ.