Objective To study the protective effect of lycopene (LP) against diabetic retinopathy (DR) in rats and its related mechanism. Methods A single dose of streptozotocin (56 mg/kg) was injected intraperitoneally in SD rats to induce diabetes retinopathy (DR), and the 20 successful DR models were equally randomized into DR group and LP treatment group. Meanwhile, 10 normal rats served as normal control group (NC). LP group received LP gavage (60 mg/kg) once a day; NC and DR groups were gavaged with equivalent saline daily for 8 weeks. The serum levels of endothelin(ET) and calcitonin gene related protein(CGRP) were detected by using radioimmunoassay(RIA), and the expression of vascular endothelial growth factor (VEGF) in the retina was determined by immunohistochemistry and Western blotting analysis. Results The serum levels of ET and expression of VEGF in the retina were significantly increased in DR groups when compared with NC group (P<0.05), and the serum CGRP was significantly decreased (P<0.05); Compared with DR group, LP group had significantly lower VEGF expression and ET levels and significantly higher level of CGRP (P<0.05). Conclusion LP can protect against DR in rats by decreasing serum ET, increasing serum CGRP, and subsequent down-regulating VEGF expression.