Objective To investigate the role of Shh-PARP-1 signaling pathway in the protective effects of tea polyphenols against the fatty acid-induced islet microvessel endothelial function injury. Methods Mouse islet microvessel endothelial MS-1 cells were used in this study, and the cells were divided into normal control group, solvent group, fatty acid group (0.25 mmol/L palmitic acid+0.5 mmol/L oleic acid), tea polyphenols group (25 μmol/L), fatty acid+tea polyphenols group, PARP-1 inhibitor (8 μmol/L BYK204165)+fatty acid group, PARP-1 inhibitor+fatty acid+tea polyphenols group, Shh inhibitor (2.5 μmol/L cyclopamine)+fatty acid group, Shh inhibitor+fatty acid+tea polyphenols group and inhibitors of Shh and PARP-1+ fatty acid +tea polyphenols group. The changes of cell viability, apoptosis, nitric oxide (NO) synthesis and oxidative stress related indicators were examined in each group. Results After fatty acid treatment, the survival rate of MS-1 cells was decreased, and the level of apoptosis was significantly increased (P<0.05); meanwhile, fatty acid treatment also significantly increased the content of NO, and the activities of total nitric oxide synthase (tNOS), inducible NOS (iNOS) and constitutive NOS (cNOS) in the cells (P<0.05). Moreover, the lipid peroxidation product, malondialdehyde (MDA) was remarkably elevated and the levels of antioxidants, glutathione (GSH) and superoxide dismutase (SOD), were significantly decreased in response to fatty acid (P<0.05); the expression of PARP-1 and phosphorylated Shh (pShh) was significantly increased (P<0.05). Tea polyphenols could significantly attenuate the toxic effects of fatty acids concerning all the detected indicators (P<0.05). Moreover, after pretreatment with Shh-PARP-1 inhibitors BYK204165 and cyclopamine for 1 h, the protective effects of tea polyphenols were markedly enhanced. There were no significant difference in the detected indicators as compared with controls (P>0.05). Conclusion Fatty acid can directly trigger islet microvessel endothelial function injury, and tea polyphenols shows a protective effect against the toxicity of fatty acid, which can be enhanced by inhibiting Shh-PARP-1 signal pathway.