Background <p>Cognitive impairment is a common complication of type 2 diabetes mellitus (T2DM); however, its underlying mechanisms are unclear. This study investigated the association between serum moesin levels, cognitive impairment, and glucose fluctuations in T2DM patients.</p> Methods <p>A total of 229 T2DM patients and 150 healthy controls were enrolled, and patients with T2DM were further categorized into those with mild cognitive impairment (MCI, <i>n</i> = 71) and without MCI (non-MCI, <i>n</i> = 158). An enzyme-linked immunosorbent assay (ELISA) was used to evaluate the serum levels of moesin, high-sensitivity C-reactive protein (hs-CRP), and brain-derived neurotrophic factor (BDNF) in all participants.</p> Results <p>Serum moesin levels were significantly elevated in T2DM patients compared to those in healthy controls (<i>P</i> &lt; 0.001) and further increased in the MCI group compared to those in the non-MCI group (<i>P</i> &lt; 0.001). Receiver operating characteristic (ROC) analysis identified an optimal moesin cutoff of 113.49 ng/mL (AUC = 0.866) for distinguishing MCI from T2DM, with 76.1% sensitivity and 86.7% specificity. Correlation analysis demonstrated that moesin was positively correlated with triglyceride, LDL-C, IMT, hs-CRP, and glucose variability markers (MAGE, MBG, SD, and MODD) but negatively correlated with years of education, BDNF, time in range (TIR), and Montreal Cognitive Assessment (MoCA) scores (<i>P</i> &lt; 0.05). Multivariate logistic regression identified BMI, years of education, diabetes duration, FBG, hs-CRP, BDNF, MAGE, SD, and moesin as independent predictors of MCI in T2DM (<i>P</i> &lt; 0.05).</p> Conclusions <p>These findings suggest that elevated serum moesin levels are associated with cognitive impairment in patients with T2DM, potentially mediated by glucose fluctuations, inflammation, and vascular dysfunction.</p>