Quercetin exerts antihypertensive effects, while its role on hypertensive renal injury remain unknown. Network pharmacology analysis identified multiple potential candidate targets (including TP53, Bcl-2 and BaX) and enriched signaling pathways (including apoptosis and p53 signaling pathway). Hematoxylin and eosin staining revealed that quercetin treatment reduced the pathological changes in renal tissues of Ang II infused mice. RNA sequencing identified quercetin treatment significantly reversed 464 DETs and enriched several signaling pathway (including apoptosis and p53 pathways). Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling staining and Annexin V staining revealed that quercetin treatment reduced cell apoptosis in renal tissues of Ang II-infused mice and in NRK-52E cells stimulated with Ang II. Furthermore, immunohistochemistry and western-blotting indicated that quercetin treatment alleviated the upregulation of p53, BaX, cleaved-caspase-9, and cleaved-caspase-3 protein expression and the downregulation of Bcl-2 protein expression in both renal tissue of Ang II infused mice and NRK-52E cells stimulated with Ang II stimulation. Moreover, the molecular docking results indicated potential binding activity between quercetin-TP53. Quercetin treatment significantly attenuated hypertensive renal injury and cell apoptosis in renal tissues of Ang II-induced mice and Ang II stimulated NERK-52E cell, and by targeting p53 may be one of the underlying mechanisms.