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Emerging evidence implicates accelerated renal tubular epithelial cell (RTEC) senescence in renal fibrosis progression. Mitophagy protects against kidney injury. However, the mechanistic interplay between cell senescence and mitophagy in RTECs is not clearly defined. The purpose of this study was to evaluate the inhibition of RTEC senescence and renal fibrosis by quercetin and explore the underlying mechanisms. We found that quercetin attenuated RTEC senescence induced by angiotensin II (AngII) in vitro and unilateral ureteral obstruction in vivo. Moreover, we demonstrated that mitochondrial abnormalities such as elevated reactive oxygen species, decreased membrane potential, and fragmentation and accumulation of mitochondrial mass, occurred in AngII-treated RTECs. Quercetin treatment reversed these effects. Furthermore, quercetin enhanced mitophagy in AngII-treated RTECs, which was markedly reduced by treatment with mitophagy-specific inhibitors. Sirtuin-1 (SIRT1) was involved in quercetin-mediated PTEN-induced kinase 1 (PINK1)/Parkin-associated mitophagy activation. Pharmacological antagonism of SIRT1 in AngII-treated RTECs blocked the effects of quercetin on mitophagy and cellular senescence. Finally, quercetin alleviated kidney fibrosis by reducing RTEC senescence via mitophagy. Collectively, the antifibrotic effect of quercetin involved inhibition of RTEC senescence, possibly through activation of SIRT1/PINK1/Parkin-mediated mitophagy. These findings suggest that pharmacological elimination of senescent cells and stimulation of mitophagy represent effective therapeutic strategies to prevent kidney fibrosis. Unlabelled Image • Renal tubular epithelial cell senescence is implicated in renal fibrosis progression. • Mitophagy has a protective role against renal fibrosis. • Quercetin reduced renal tubular epithelial senescence by activating SIRT1. • Quercetin activated SIRT1/PINK1/Parkin-mediated mitophagy. • Quercetin attenuated renal fibrosis via enhancing SIRT1-PINK1/Parkin. [ABSTRACT FROM AUTHOR]