Objective: To investigate the effect of human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exs) on diabetic retinal neurodegeneration (DRN).Methods: Exosomes were isolated from human umbilical cord mesenchymal stem cells (hucMSC) and identified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and Western blotting (WB). Rats were intraperitoneally injected with Streptozotocin (STZ) to establish a diabetes mellitus model, and blood glucose levels and body weight were assessed. The rats were intravitreally injected with phosphate buffered saline (PBS; diabetic group) or hucMSC-Exs (hucMSC-Exs group). A control group of rats were not treated with STZ and were intravitreally injected with PBS (normal control group). Hematoxylin-eosin (HE) staining was used to observe changes in retinal structure and to count the number of retinal ganglion cells (RGCs) four weeks after intravitreal injection. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay (TUNEL) was used to detect retinal cell apoptosis. The retinal expression of p38 mitogen-activated protein kinase (p38MAPK), phosphorylated p38MAPK (p-p38MAPK), Bcl-2 and Bax was measured using WB to investigate the mechanism by which hucMSC-Exs affects DRN.Results: Using TEM, NTA and WB, hucMSC-Exs were successfully isolated. No significant change was observed after injection in the normal control group. All rats injected with STZ developed hyperglycemia. HE staining revealed that hucMSC-Exs effectively alleviated retinal structure disruption and reduced the apoptosis of RGCs (P < 0.05). Cells positive for TUNEL (TUNEL+) occurred at a higher rate in the diabetic group than in other groups (P < 0.05). Compared with the normal control group, the expression of p-p38MAPK was significantly increased in the diabetic group and decreased in the hucMSC-Exs group (P < 0.01). The expression of Bax was significantly decreased while Bcl-2 expression was significantly increased in hucMSC-Exs group (P < 0.01).Conclusion: These findings suggest that intravitreal injection of hucMSC-Exs can reduce DRN and protect retinal structure, and that these effects are mediated through inhibition of the p38MAPK pathway.