Purpose: To verify the mediating role of inflammatory factors in plasma fatty acid-induced changes in cognitive function in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: In this study, we evaluated the cognitive function of 372 Chinese patients (the average age was 58.00 (52.50, 63.00) years) with T2DM by using the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), with plasma fatty acids measured by gas chromatography analysis and inflammatory cytokines determined by immune turbidimetric analysis and enzyme-linked immunosorbent assay (ELISA) to investigate whether there was a correlation between the plasma fatty acids, inflammatory cytokine levels and cognitive test scores in Chinese patients with T2DM. Results: We found that the increase of waist circumference and hip circumference might lead to cognitive impairment and induce the inflammatory response. Higher saturated fatty acids (SFAs) levels in plasma were linked to cognitive decline, while higher monounsaturated fatty acids (MUFAs) intake might be a protective factor for cognitive function. In addition, higher levels of plasma n-6 polyunsaturated fatty acids (n-6 PUFAs) stood out as having association with lower cognitive function scores, while higher level of plasma C22:6 n-3 could be a predictor of better cognitive function. In our study, higher SFAs led to higher proinflammatory factor levels. Apart from that, MUFAs and stearoyl-CoA desaturase-18 (SCD-18) were positively related to hypersensitive C-reactive protein (hs-CRP). Meanwhile, higher level of plasma C20:0 could lead to better MMSE delayed recall by reduce the expression of hs-CRP. Conclusion: Levels of plasma SFAs, C18:3 n-6, and C20:3 n-6 could be a predictor for worse cognitive function, while MUFAs and C22:6 n-3 could be a predictor for better cognitive function. The level of hs-CRP could be a mediator of C20:0 induced the change of cognitive function.