Antioxidants represented by kaempferol have been shown to be effective against atherosclerosis (AS). However, the underlying mechanisms still remain unclear. The aim of this research was to reveal the mechanism of kaempferol regarding the treatment of AS and accumulation of foam cell. We explored the contribution of kaempferol to the levels of inflammatory factors, scavenger receptor CD36, mitochondrial membrane potential, ROS, MAPK/NF-κB, Nrf2/HO-1, Ca²⁺ and Piezo1 levels in RAW264.7 macrophages exposed to ox-LDL. In addition, to explore whether kaempferol inhibits ox-LDL-induced foamy macrophage through Piezo1, we extracted macrophages from Piezo1 macrophage-specific knockout (Piezo1^ΔLysM) mice. For further validation, ApoE^-/- and Piezo1 macrophage-specific knockout mice (Piezo1^ΔLysM/ ApoE^-/-) were generated. The results showed that kaempferol notably suppressed inflammatory response, CD36 expression, mitochondrial membrane potential elevation, ROS production, MAPK/NF-κB expression, Ca²⁺ expression, and increased Nrf2/HO-1 levels in RAW264.7. In addition, depletion of macrophage Piezo1 also effectively reduced lipid droplet deposition, inflammatory factor expression, oxidative damage, MAPK/NF-κB, Ca²⁺ expression, and increased Nrf2/HO-1 expression in mouse BMDMs, and the results were still consistent after kaempferol treatment. In vivo studies have shown that kaempferol significantly reduces atherosclerotic plaque formation. However, the beneficial effect of kaempferol was attenuated in Piezo1 depletion mice. These results collectively provide compelling evidence that kaempferol regulates CD36-mediated mitochondrial ROS production by inhibiting the Piezo1 channels and Ca²⁺ influx, and then regulates the downstream pathways of NF-κB/MAPK and HO-1/Nrf2, inhibiting to the formation of foam cells. In conclusion, this study revealed a potential mechanism by which the natural antioxidant kaempferol prevents foamy macrophage.