Quercetin exerts anti‐oxidative and anti‐inflammatory activity by regulating the SIRT1/FOXO3A and p38 signaling pathways. (a) Molecular docking results showing Que in the FOXO3A binding site. Que is shown as a green stick; the protein surface is colored by its electrostatic potential from red (−69.961) to blue (69.961). (b) Hydrogen bonds (green dashed lines) and hydrophobic interactions (red “eyelashes”) shown using LIGPLOT v2.2.4. (c) The knockdown effect of FOXO3A in R28 cells. (d) Cell viability (evaluated by ATP content) with or without the knockdown of FOXO3A. Data are presented as mean ± SD (n = 3); *p < 0.05 compared with the control group. (e, f) Representative western blots for FOXO3A, SIRT1, SOD1, BCL2, BAX, cleaved Caspase 3, p‐p38 and p38 in R28 cells with or without Que@TPP‐ROS‐Lips after OGD. GAPDH was used as the loading control. (n = 3). (g) The bar graphs represent the of Western blots illustrating the significant Que@TPP‐ROS‐Lips mediated amelioration of OGD‐induced changes in FOXO3A/SIRT1 pathway proteins (FOXO3A, SIRT1, and SOD1), p38 pathway proteins (p‐p38 and p38) and apoptosis‐associated proteins (BCL2, BAX, and Cleaved Caspase 3) in R28 cells treated with or without Que@TPP‐ROS‐Lips. (h) Representative immunofluorescence images of FOXO3A, SIRT1, p‐p38, and p38 in retinal cryosections indicating that Que@TPP‐ROS‐Lips‐mediated enforcement in levels of FOXO3A and Sirt1 and reduction in the level of p‐p38 in ischemic retina compared to saline group. (scale bar = 50 μm; n = 6). *p < 0.05 compared with the control group.