Objective To investigate the high-sensitivity C-reactive protein (hs-CRP) and endostatin (ES) in early diagnosis of diabetic limb gangrene (DG). Methods A total of 106 T2DM patients were divided into simple diabetic group (DM) and early diabetic gangrene group (DG group). hs-CRP was measured using ultra-sensitive latex-enhanced scattering immunoturbidimetric assay. ES was determined by ELISA. Their value in diagnosis of DG was detected. Results DAN, LEAD, MAU, ABI, LDL-C, hs-CRP, VEGF and ES levels in the DG group were higher than those of the DM group (P < 0.05). The Ou Mino discoloration started earlier and the complete discoloration time was longer in the DG group than in the DM group (P < 0.05). Spearman correlation analysis showed that hs-CRP was positively correlated with DAN, LEAD, VEGF, ES and LDL-C (r = 0.486, 0.477, 0.505, 0.503 and 0.473, respectively; P < 0.05), but was in a negative correlation with ABI (r = -0.488, P < 0.05); ES was negatively correlated with DAN, LEAD, VEGF and hs-CRP (r = -0.507, -0.501, -0.492 and -0.508; P < 0.05), but positively correlated with ABI(r = 0.497, P < 0.05). The sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy and AUC of the combination of ES and hs-CRP were higher than those of ES and hs-CRP alone in diagnosis of DG. Conclusions ES and hs-CRP have significant correlations with DG and autonomic neuropathy. ES combined with hs-CRP has high diagnostic value for DG.