Objective To investigate the protective effect of intraperitoneal injection of quercetin (QU) on retinal ischemia-reperfusion injury (RIRI) rats and its mechanism. Methods The random number method was used to divide 96 adult male SPF-grade rats without ocular disease into the control group (6 rats), the RIRI group (30 rats), the negative control group (30 rats), and the QU group (30 rats). At 7 consecutive days before modeling and 10 minutes before modeling, the rats in the QU group underwent the intraperitoneal injection of QU, the rats in the RIRI group underwent the intraperitoneal injection of an equal volume of normal saline, rats in the negative control group were intraperitoneally injected with an equal volume of DMSO, and rats in the control group were not treated. In addition to the control group, the ocular hypertension method was used to establish the RIRI models in the RIRI group, the QU group, and the negative control group. Rat retinal tissue specimens were prepared at 6, 12, 24, 48, and 72 h after modeling. Changes in the histomorphology of the rat retina were observed by hematoxylin-eosin (HE) staining, and the thickness of the inner layer of the rat retinal tissues was measured by a computerized image analysis system. Retinal apoptosis was observed by the TUNEL method. The expression of cysteine containing Caspase-3 was detected by immunohistochemistry. Results The retinal cells at each layer were normal in rats of the control group. The retinas of rats in the RIRI group and the negative control group showed a high degree of edema after 6 h of modeling; the number of ganglion cells in the retina was reduced and the arrangement of ganglion cells and inner nuclear layer cells was disorganized after 12 h of modeling; the edema of the retina was reduced after 24 h of modeling and the structure of the cells was further disrupted; and the edema of the retina was basically disappeared and the number of ganglion cells and inner nuclear layer cells was reduced after 48 h of modeling. The QU group had more intact retinal tissue structure and less cellular damage compared with the RIRI group and the negative control group at all time points. At 6 h and 12 h after modeling, the inner layer thickness of the retina was as follows: RIRI group, negative control group>QU group>control group, at 24 h, it was QU group>RIRI group, negative control group >control group, and at 48 and 72 h, it was control group>QU group>RIRI group, negative control group (all P<0. 05). In the control group, apoptotic cells and Caspase-3 positive cells were occasionally expressed in the rat retinal tissues. In the RIRI and negative control groups, the number of apoptotic cells and the number of Caspase-3 positive cells in the rat retinal tissues gradually increased at 6, 12, and 24 h of modeling, reached peak at 24 hs, and gradually decreased at 48 and 72 h. At each time point, the number of apoptotic cells and the number of caspase-3 positive cells in the rat retinal tissues of the QU group showed the same trend as that of the RIRI group and the negative control group, but the numbers were smaller than those of the RIRI group and the negative control group at the same time point (all P<0. 05). Conclusion Intraperitoneal injection of QU in rats has a certain protective effect against RIRI, and the mechanism may be related to the reduction of positive expression of Caspase-3 and inhibition of apoptosis. [ABSTRACT FROM AUTHOR]