Diabetic nephropathy (DN) is a common secondary kidney disease. Immune and inflammatory responses play an influential role in the development of DN. This study aims to explore the role and mechanisms of immune- and inflammatory-related factors in DN. Participants from the NHANES 2013-2018 were included to evaluate the association between the SII and DN. Considering the skewed distribution of SII, log SII was used for subsequent analysis. Then, the DEGs were extracted from the GSE96804 dataset by the "limma" package of R, which were further screened out genes in the key module based on WGCNA. The intersection genes between DEGs and key module genes were the key genes for the following mechanism exploration. The CyTargetlinker plug-in of Cytoscape software was used to construct the drug-genes network. Molecular docking was used to calculate the binding affinity between potential drugs and the hub genes. Among the 8236 participants from NHANES 2013-2018, Log SII was significantly associated with DN (p < 0.05). DEG and WGCNA revealed 30 DN-related genes, which mainly regulated immune- and inflammation pathways, and the NOD-like receptor signaling pathway was the core pathway highly involved in the DN occurrence. Moreover, NAIP, ZFP36, and DUSP1 were identified as hub genes in DN progression and there was a strong binding interaction between resveratrol and DUSP1.In conclusion, immune inflammation plays an influential role in the occurrence and development of DN. SII is an effective diagnostic marker for DN and resveratrol might have potential value in treating DN.