The apoptosis plays a critical role in a number of inflammatory disorders. Bacterial infection is one of the causes inducing apoptosis. This study aims to investigate the mechanism by which activation of TLR5 induces podocyte apoptosis. In this study, a podocyte cell line was cultured in RPMI1640 medium. The expression of TLR5 was assessed by real‐time PCR and Western blotting. The Fas ligand gene transcription was assessed by immunoprecipitation and chromatin immunoprecipitation assay. The results showed that the expression of TLR5 was observed in the podocytes at both mRNA and protein levels. Exposure to TLR5 ligand, flagellin, induced Fas ligand expression and podocyte apoptosis. p300, one of the histone acetyltransferases, mediated the Fas ligand gene transcription in podocytes. In conclusion, TLR5 activation plays an important role in the induction of podocyte apoptosis. Copyright © 2016 John Wiley & Sons, Ltd.