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Inflammation has been recognized as a pivotal factor in the pathophysiology of diabetes. The aggregate index of systemic inflammation (AISI) has recently been proposed as a novel biomarker for evaluating inflammatory status and predicting clinical outcomes. However, evidence on the association between AISI and mortality in diabetic patients remains limited. To address this knowledge gap, we aimed to investigate the association between AISI and mortality risk from cardio-cerebrovascular disease (CCD) and malignant neoplasms in diabetic patients. We analyzed data from the National Health and Nutrition Examination Survey (NHANES, 2001-2018). Multivariable-adjusted Cox models revealed strong associations between elevated AISI levels and CCD mortality (HR 1.18, 95% CI 1.11-1.26) as well as malignant neoplasm mortality (HR 1.20, 95% CI 1.10-1.30). Kaplan-Meier analysis showed that higher AISI was associated with lower survival in diabetic patients for both CCD and malignant neoplasms. Restricted cubic spline (RCS) analysis demonstrated an increased risk of mortality from CCD and malignant neoplasms in diabetic patients with elevated AISI levels. Subgroup and sensitivity analyses confirmed the robustness of these findings. In adults with diabetes, elevated AISI levels are strongly associated with an increased risk of mortality from CCD and malignant neoplasms.