Background <p>The role of nutritional status, particularly the risk of malnutrition as quantified by the Geriatric Nutritional Risk Index (GNRI), in the development of diabetic nephropathy (DN) among patients with type 2 diabetes mellitus (T2DM) remains to be fully elucidated. Thus, this study aimed to investigate the cross-sectional association between GNRI-assessed nutritional risk and DN and to explore the potential mediating role of inflammatory markers.</p> Methods <p>A total of 675 hospitalized T2DM patients were enrolled. Multivariate logistic regression was used to determine whether GNRI is independently associated with DN. A restricted cubic spline (RCS) curve was used to visualize the association between GNRI and DN, and exploratory mediation analysis was conducted to assess the roles of systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR).</p> Results <p>Of the 675 T2DM patients, 190 (28.1%) were diagnosed with DN. Compared with individuals without DN, the GNRI score was significantly lower in the DN group (<i>P</i> &lt; 0.001). Multivariate logistic regression analysis revealed that compared with the lowest tertile (T1) of GNRI, the highest tertile (T3) was significantly associated with a lower prevalence of DN (OR 0.53, 95%CI 0.31–0.89, <i>P</i> = 0.017). The RCS curve demonstrated a significant linear inverse association between higher GNRI scores and DN (<i>P</i> = 0.006). Mediation analysis suggested that SII and NLR statistically mediated 13.60% and 7.51% of the association between GNRI and DN, respectively.</p> Conclusion <p>In this cross-sectional study, lower GNRI scores were independently associated with DN in T2DM patients, and systemic inflammation partially explained this association. GNRI may serve as a potential and readily available clinical marker for nutritional-inflammation risk screening in this population.</p> Clinical trial number <p>Not applicable.</p>