Background <p>This study analyzed the data from a previous randomized clinical trial to investigate the effects of intranasal insulin on postoperative delirium (POD) in older patients with and without type 2 diabetes mellitus (T2DM).</p> Materials and methods <p>This study included 128 older surgical patients, stratified into diabetes mellitus (DM, <i>n</i> = 50) and non-diabetes (Non-DM, <i>n</i> = 78) cohorts. Patients received either perioperative intranasal insulin or saline. The primary outcome was POD incidence; secondary outcomes included the perioperative changes Mini-Mental Status Examination (MMSE) scores and the Montreal Cognitive Assessment-Basic (MoCA-B) scores. Logistic and linear regression models were used to evaluate the association between intranasal insulin and outcomes within each subgroup. Additionally, sensitivity analyses adjusting for different covariates were performed to evaluate the consistency.</p> Results <p>The incidences of POD in Group DM-S (DM + saline, <i>n</i> = 22), Group DM-I (DM + insulin, <i>n</i> = 28), Group Non-DM-S (non-DM + saline, <i>n</i> = 42), Group Non-DM-I (non-DM + insulin, <i>n</i> = 36) were 36.4%, 10.7%, 19% and 11.1%, respectively. Intranasal insulin was associated with reduced POD risk in T2DM patients (adjusted OR = 0.195, 95% CI: 0.036–0.826, <i>P</i> = 0.035), but not significant in non-T2DM patients. Additionally, insulin positively correlated with perioperative changes of MMSE and MoCA-B scores in both T2DM (MMSE: β = 1.042, 95% CI: 0.230–1.854, <i>P</i> = 0.013; MoCA-B: β = 1.093, 95% CI: 0.013–2.173, <i>P</i> = 0.047) and non-T2DM cohorts (MMSE: β = 0.748, 95% CI: 0.124–1.373, <i>P</i> = 0.019; MoCA-B: β = 0.887, 95% CI: 0.116–1.658, <i>P</i> = 0.025). Sensitivity analyses yielded consistent trends.</p> Conclusion <p>Intranasal insulin was associated with reduced POD incidence in older patients with T2DM and exhibited a potential protective effect on postoperative cognition.</p>