Hidradenitis suppurativa (HS) is an autoinflammatory keratinization disease affecting the pilosebaceous unit and hallmarked by a complex and multifactorial pathogenesis. In recent years, genetics and transcriptomics have been advancing in elucidating several crucial mechanisms underlying HS pathogenesis. Proteomic studies remain scarce, although serum proteomics holds great potential for capturing molecular signatures that reflect both cutaneous and systemic inflammation. This study presents a serum proteomic analysis of patients with moderate-to-severe HS, identifying 432 differentially expressed proteins out of 3,153 profiled. Enrichment analyses revealed dysregulated pathways related to keratinization, epidermal differentiation, and extracellular matrix remodeling, indicating impaired skin barrier function. Concurrent upregulation of immune-related pathways, including antibacterial responses and neutrophil degranulation, suggests systemic inflammation potentially linked to microbial dysbiosis. These findings support the dual role of epithelial dysfunction and autoinflammation in HS pathogenesis. Integration of proteomic data with genomic and transcriptomic findings underscores the value of multi-omics approaches in guiding targeted therapeutic development.