Aim A diverse combination of etiologies such as vascular and inflammatory factors and social and physical inactivity may take place in the etiology of cognitive dysfunction (CD). Diabetes mellitus (DM) may contribute to CD over insulin resistance, inflammation, and vascular risk factors. However, mechanisms included in the process are not very clear. We aimed to investigate serum levels of selected biomarkers as a proliferation-inducing ligand (APRIL), FGF-21, P-selectin, soluble vascular cell, and intercellular adhesion molecules-1 (sVCAM-1 and sICAM-1) in elderly patients with DM in relation to cognitive function. Methods A group of 80 elderly type 2 diabetic patients from the outpatient clinic, consisting of 40 patients with CD (mini-mental state examination (MMSE) score < 24) and 40 individuals without CD were enrolled in the study. Anthropometric, sociodemographic, and functional-glycemic evaluations were determined. Biomarker levels were determined by enzyme-linked immunosorbent assay. Results Median sICAM-1 and FGF-21 levels were higher, and P-selectin level, activities of daily living (ADL), instrumental ADL, MNA, and MMSE scores were lower in the CD group (p = 0.002,p = 0.010,p = 0.001,p = 0.001,p < 0.001,p = 0.005,p < 0.001, respectively). There was no significant difference between the groups regarding age, gender, living status, education, cigarette and alcohol consumption, antidiabetic therapy as well as comorbidities such as hypertension and other diseases, depression, body composition, sVCAM-1, APRIL levels, and related biochemical values. Conclusion Median sICAM-1 and FGF-21 levels were higher and P-selectin level was lower in older diabetic patients with CD than in patients with normal cognitive status. Understanding the mechanisms may lead to the prevention or delay of CD in those patients.