<p>Insulin resistance arises from impaired insulin signaling, leading to reduced glucose uptake and the progression of type 2 diabetes mellitus. Experimental evidence indicates that lithium modulates insulin signaling pathways; however, its role in the development of insulin resistance remains poorly defined. Anthropometric, biochemical, and lifestyle data were collected. IR was assessed via HOMA-IR, and insulin processing/clearance was evaluated by insulin to c-peptide ratio (ICPR). Univariate and multivariate logistic regression identified independent predictors of IR. ROC analysis assessed the diagnostic performance of Li. Linear regression examined associations between biochemical parameters and IR. A cross-sectional study was conducted among 211 adults with T2D attending AIIMS Raebareli; of these, 172 participants with complete data constituted the final analytical cohort, including 122 (70.9%) with insulin resistance (IR). The IR group exhibited significantly higher fasting and postprandial glucose, insulin, C-peptide, ICPR, total cholesterol, and TyG index, and lower serum lithium levels than the non-IR group. Multivariate logistic regression analyses identified ICPR, TyG index, and serum lithium (OR = 3.69, 95% CI: 1.190-11.437, <i>P</i> = 0.024) as independent predictors of IR. ROC analysis showed that a lithium cutoff of 0.1 mmol/L predicted IR, with 81.9% sensitivity and 56.5% specificity (AUC = 0.863). Lower lithium levels were associated with higher insulin, C-peptide, and ICPR, and linear regression revealed a significant inverse association between lithium and HOMA-IR (β = −0.233, <i>p</i> = 0.007). Lower serum lithium levels independently predict insulin resistance in T2DM, alongside ICPR and TyG index. This association with hyperinsulinemia and impaired insulin processing/clearance suggests a potential mechanistic role for lithium in metabolic dysregulation.</p>