Objective To investigate the correlation between the total cholesterol to high density lipoprotein cholesterol (TC/HDL-C) ratio and insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM). Methods 86 patients with T2DM admitted to our hospital from March 2023 to March 2024 were retrospectively collected and included into the observation group, 86 healthy subjects who underwent physical examination in our hospital during the same period were included in the control group. The levels of fasting plasma glucose (FPG), fasting insulin (FINS), and homeostasis model assessment of insulin resistance (HOMA-IR) in two groups and patients with different HOMA-IR levels were analyzed and compared. The correlation between HOMA-IR levels and TC, TC/HDL-C in patients with T2DM was analyzed. Results In the observation group, TG, LDL-C, HbAlc, FPG, FINS, and HOMA-IR were higher than those in the control group, while lymphocytes were lower, with statistically significant differences (P<0.05). Patients with high levels of HOMA-IR had higher TG, LDL-C, HbAlc, FPG, FINS, and HOMA-IR than those with low levels of HOMA-IR, with statistically significant differences (P<0.05). Compared with patients with low levels of HOMA-IR, those with high levels of HOMA-IR had significantly higher TC and TC/HDL-C ratio, and significantly lower HDL-C levels, with statistically significant differences (P<0.05). The level of HOMA-IR in patients was positively correlated with TC and TC/HDL-C ratio, and negatively correlated with HDL-C, with statistically significant differences (P<0.05). Conclusion The TC/HDL-C ratio in patients with T2DM is associated with the level of HOMA-IR and is closely related to the occurrence of IR in these patients.