Abstract：Objective：To investigate the action mechanism of Huoxue Tongluo Prescription regulating phosphoinositide 3- kinase/protein kinase B(PI3K/Akt) signaling pathway to improve diabetic retinopathy in rats. Methods： A total of 72 clean grade healthy male SD rats were selected and divided into the control group， the model group and the medication group according to the random number table method， with 24 rats in each group. After successful modeling，the medication group was given 10 mL/(kg·d) of Huoxue Tongluo Prescription by gastric irrigation，and the control group and the model group were given the same dose of 0.9% sodium chloride injection by gastric irrigation. All the three groups were given continuous gastric irrigation for three months. The levels of blood glucose， blood lipid， oxidative stress indexes and inflammatory factors as well as the permeation quantity of Evans Blue in the three groups were compared； the expression levels of zonula occludens protein-1(ZO-1)，occludin，vascular endothelium-cadherin(VEcadherin)， phosphorylated phosphoinositide 3-kinase(p-PI3K) and phosphorylated protein kinase B(p-Akt) in retinal tissues of rats in the three groups were compared；the histopathological changes of retinal tissues in rats were observed. Results： When compared with those in the control group， the levels of fasting blood glucose(FBG)，glycosylated hemoglobin(HbA1c)，total cholesterol(TC)，triglyceride(TG)，low density lipoprotein(LDL)， reactive oxygen species(ROS)， malondialdehyde(MDA)， glutathione peroxidase(GSHPx)， interleukin- 6(IL- 6)，interleukin- 1β(IL- 1β) and tumor necrosis factor- α(TNF- α) in the model group were raised(P＜0.05)，levels of high density lipoprotein(HDL) and superoxide dismutase(SOD) in the model group were reduced(P＜0.05)，and the permeation quantity of Evans Blue in the model group was increased (P＜0.05). When compared with those in the model group， the levels of FBG， HbA1c， TC， TG， LDL， ROS，MDA，IL- 6，IL- 1β and TNF- α in the medication group were reduced(P＜0.05)，levels of HDL ， SOD and GSH-Px in the medication group were increased(P＜0.05)，and the permeation quantity of Evans Blue in the medication group was decreased(P＜0.05). When compared with those in the control group， the expression levels of ZO-1，occludin and VE-cadherin in retinal tissues of rats in the model group were decreased(P＜0.05)，and the expression levels of p-PI3K and p-Akt in the model group were increased(P＜ 0.05). When compared with those in the model group ， the expression levels of ZO- 1， occludin and VE-cadherin in retinal tissues of rats in the medication group were increased(P＜0.05)，and the expression levels of p- PI3K and p- Akt in the medication group were decreased(P＜0.05). In the model group， the retinal tissue cells were disordered and loose in arrangement，the pigment epithelial cells proliferated，the capillaries were obviously dilated and congested，and new blood vessels appeared in the outer layer. When compared with those in the model group， the retinal tissue cells in the medication group were arranged neatly and the density was increased， and the retinal pathological changes were significantly reduced. Conclusion： Huoxue Tongluo Prescription can alleviate inflammatory responses and improve oxidative stress by inhibiting PI3K/Akt signaling pathway，thus improving diabetic retinopathy in rats.