Aim To investigate the correlation between serum Nesfatin-1, heat shock protein 60 (HSP60) and lower extremity vascular disease (LEVD) in patients with type 2 diabetes (T2DM). Methods A total of 120 T2DM patients were selected and divided into two groups according to whether the lower extremity vascular ultrasound examination was combined with LEVD, 62 cases in the LEVD group, 58 cases in the non-LEVD group, and the other fifty healthy subjects were selected as the control group, the serum Nesfatin-1 and HSP60 levels of all subjects were measured, and the relationship between serum Nesfatin-1, HSP60 levels and LEVD in T2DM patients was analyzed. Results The serum Nesfatin-1 level was significantly lower in the LEVD group than that in the non-LEVD group, and the HSP60 level was significantly higher than that in the non-LEVD group (P＜0.05); the serum Nesfatin-1 level in patients with different LEVD grades decreased with the increase of the disease grade, and the HSP60 level increased with the increase of lesion grade (P＜0.05); Pearson correlation analysis showed that body mass index (BMI), waist to hip ratio (WHR), glycosylated hemoglobin (HbA1c), fasting blood glucose (FPG), fasting insulin (FINS), insulin resistance index (HOMA-IR), low-density lipoprotein cholesterol (LDLC), alanine aminotransferase (ALT), serum creatinine (SCr), blood urea nitrogen (BUN) levels were negatively correlated with Nesfatin-1 level, and positively correlated with HSP60 levels; high-density lipoprotein cholesterol (HDLC) levels were positively correlated with Nesfatin-1 level, and negatively correlated with HSP60 level (P＜0.05); multivariate stepwise Logistic regression analysis showed that Nesfatin-1, HSP60 was independent influencing factors of T2DM patients with LEVD (P＜0.05). Conclusions Serum Nesfatin-1 level in T2DM patients combined with LEVD were significantly reduced, and HSP60 levels were significantly increased, and changed with the severity of the disease. They are independent factors affecting LEVD. Early detection of serum Nesfatin-1 and HSP60 levels can help prevent LEVD in time.