Interestingly, we found that LPS, a TLR4 ligand, or bacterial infection triggers assembly of the complexes of Piezo1 and TLR4 to remodel F-actin organization and promote phagocytosis, mitochondrion–phagosome juxtaposition for ROS production and bacterial clearance, whereas knockout of Piezo1 impairs these responses. Here, PIEZO1 is linked to bacterial infectious disease.