Diabetic foot (DF) and its complications represent a growing public health challenge, significantly impacting morbidity and mortality in the global diabetic population. The pathogenesis of DF is complex, involving multiple systemic and local factors that impede wound healing and exacerbate tissue damage. In this study, we conducted an in-depth proteomic analysis of diabetic foot skin (DFS) and non-diabetic foot skin (NFS) samples, revealing substantial differences in protein expression profiles. Principal component analysis (PCA) highlighted these differences, with a significant number of proteins differentially expressed, particularly those involved in neutrophil degranulation, coagulation, and angiogenesis. Further analysis identified 449 proteins with significant expression changes, 244 of which were upregulated in DFS. Functional enrichment using Metascape indicated a pronounced involvement of neutrophil extracellular traps (NETs) and related immune responses, which have been implicated in diabetic complications. To corroborate these findings, we integrated public gene expression datasets, identifying 18 key proteins linked to DF pathology. Molecular docking studies further identified MDL-28170 and amlexanox as potential therapeutic agents targeting these proteins, with strong binding affinities suggesting promising therapeutic efficacy. Our findings emphasize the critical role of neutrophil dysfunction in DF and offer new avenues for targeted treatment strategies. However, the study’s limitations, including a small sample size and the need for further in vivo validation, highlight the importance of ongoing research to translate these findings into clinical applications.