OBJECTIVE Relative to European Americans, African Americans manifest lower levels of computed tomography–based calcified atherosclerotic plaque (CP), a measure of subclinical cardiovascular disease (CVD). Potential relationships between CP and cerebral structure are poorly defined in the African American population. We assessed associations among glycemic control, inflammation, and CP with cerebral structure on MRI and with cognitive performance in 268 high-risk African Americans with type 2 diabetes. RESEARCH DESIGN AND METHODS Associations among hemoglobin A1c (HbA1c), C-reactive protein (CRP), and CP in coronary arteries, carotid arteries, and the aorta with MRI volumetric analysis (white matter volume, gray matter volume [GMV], cerebrospinal fluid volume, and white matter lesion volume) were assessed using generalized linear models adjusted for age, sex, African ancestry proportion, smoking, BMI, use of statins, HbA1c, hypertension, and prior CVD. RESULTS Participants were 63.4% female with mean (SD) age of 59.8 years (9.2), diabetes duration of 14.5 years (7.6), HbA1c of 7.95% (1.9), estimated glomerular filtration rate of 86.6 mL/min/1.73 m2 (24.6), and coronary artery CP mass score of 215 mg (502). In fully adjusted models, GMV was inversely associated with coronary artery CP (parameter estimate [β] −0.47 [SE 0.15], P = 0.002; carotid artery CP (β −1.92 [SE 0.62], P = 0.002; and aorta CP [β −0.10 [SE 0.03] P = 0.002), whereas HbA1c and CRP did not associate with cerebral volumes. Coronary artery CP also associated with poorer global cognitive function on the Montreal Cognitive Assessment. CONCLUSIONS Subclinical atherosclerosis was associated with smaller GMV and poorer cognitive performance in African Americans with diabetes. Cardioprotective strategies could preserve GMV and cognitive function in high-risk African Americans with diabetes.