A retrospective cross-sectional study included 2177 patients with type 2 diabetes mellitus (T2DM) and 327 age- and sex-matched healthy controls. Insulin resistance (IR) was assessed by the HOMA-IR index, and T2DM patients were divided into groups with IR or without IR. The markers of systemic inflammation examined—neutrophil-to-lymphocyte ratio (NLR), high-sensitivity C-reactive protein (hs-CRP), and white blood cell (WBC) count—were significantly higher in T2DM patients than in controls and even higher in those with IR. All three markers were positively correlated with HOMA-IR, with NLR having the strongest association (r = 0.280, p < 0.001). In multivariable logistic regression, NLR remained independently associated with IR after adjustment for body mass index, glycated hemoglobin, and triglycerides. ROC analysis showed for NLR the highest area under the curve (AUC = 0.670) with moderate discrimination, higher sensitivity, but lower specificity compared to hs-CRP and WBC. NLR can serve as a simple adjunctive marker of IR from a routine blood count rather than a stand-alone diagnostic tool. Prospective studies are needed to confirm the findings.