Phagosome- and xenophagosome-lysosome systems play a critical role in the defense of pathogenic bacteria, such as Salmonella and S. aureus, in macrophages. A great part of the bacteria escapes from the digestion and can survive through some mechanisms that are still poorly understood and which require further exploration. Here we identified that Salmonella inhibited the expression and activation of TFEB to blunt the functions of lysosomes and defense of clearance by activating caspase-1. The expression and activation of TFEB were enhanced early under the infection of S. aureus, which was followed by shrinkage to weaken lysosomal functions due to the delayed activation of ERK, mTOR, and STAT3. Thus, we have identified novel escape mechanisms for Salmonella and S. aureus to deepen and strengthen our strategies fighting with pathogens.