Purpose <p>This study aims to investigate the mediating role of nutritional status and the inflammatory marker C-reactive protein (CRP) in the relationship between oral frailty and cognitive function in elderly patients with chronic diseases.</p> Methods <p>A cross-sectional design was employed, and From June to December 2024, patients aged ≥ 60 years with chronic diseases from three tertiary hospitals in Henan Province were selected using convenience sampling. Data were collected using questionnaires, including the general information questionnaire, the Oral Frailty Screening Index-8 (OFI-8), the Mini Nutritional Assessment Short Form, the Montreal Cognitive Assessment, and laboratory tests for CRP. Descriptive demographic analysis and Pearson correlation analysis were conducted using SPSS 26.0, and the model 6 in macro program Process 4.1 was employed to test the chain mediation effect.</p> Results <p>(1) Regression analysis showed that oral frailty had a significant direct impact on cognitive function (<i>β</i> = -0.154, <i>P</i> &lt; 0.01), and nutritional status (<i>β</i> = 0.228, <i>P</i> &lt; 0.001) and CRP (<i>β</i> = -0.200, <i>P</i> &lt; 0.001) also had significant effects on cognitive function. (2) The results of the mediating effect analysis showed that the simple mediating effects of nutritional status and CRP between oral frailty and cognitive function were -0.088 (95% <i>CI</i>: -0.138 to -0.048) and -0.056(95% <i>CI</i>: -0.097 to -0.029), respectively, and the chain mediating effect was - 0.022 (95% <i>CI</i>: -0.040 to -0.010).</p> Conclusion <p>This study found direct and chain-mediated effects of nutritional status and CRP between oral frailty and cognitive function. It suggests that cognitive function can be improved by early identification of oral frailty, improving nutritional status and reducing chronic inflammation levels to delay or even reverse the onset and progression of cognitive dysfunction in elderly patients with chronic diseases.</p>