Acne vulgaris (AV) is a chronic inflammatory skin disease with a complex pathogenesis, and its association with insulin resistance (IR) remains unclear. This study aimed to identify differential proteins linking AV and IR to improve diagnostic and therapeutic strategies. Plasma proteomic profiling by using LC-MS/MS was performed on 90 AV patients (with IR [n = 40], without IR [n = 50]) and 30 healthy controls (with IR [n = 11], without IR [n = 19]). Differentially expressed proteins were analyzed using bioinformatics tool to identify key molecules and pathways. Candidate molecules were screened based on their positive correlations with both AV severity and insulin levels. In group AV with IR, C4BPA was highly expressed, showed strong positive correlations (Pearson's R = 0.46, p = 4.21E-6) with insulin levels and were enriched in complement agglutination cascade and B-cell-mediated immune pathways. In group AV, C4BPA (Pearson's R = 0.23, p = 0.03) also correlated with AV severity (GAGS scores) and was enriched in complement and coagulation cascades and leukocyte-mediated immunity. C4BPA acted as a key molecule, bridging IR and AV pathogenesis. This study offers a highly valuable proteomic resource for AV associated with IR and proposes a mechanistic hypothesis, supported by existing literature, that insulin exacerbates acne by regulating lipid metabolism and inflammatory pathways with C4BPA potentially acting as a central mediator in this process.