Postherpetic neuralgia (PHN) is the most prevalent form of chronic pain resulting from herpes zoster. Despite its prevalence, the molecular etiology of PHN remains poorly understood, and effective treatments are limited. In this study, we aimed to identify key serum molecules that exhibit significant differences between PHN patients and healthy controls. Using mass spectrometry-based proteomics, we identified 24 upregulated and 8 downregulated differentially expressed proteins (DEPs) in PHN patients compared to healthy controls. These dysregulated proteins are implicated in various biological processes, molecular functions, cellular components, and signaling pathways. Notably, the Rap1 signaling pathway and focal adhesion pathway were among the top pathways identified by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Key molecules including TLN1, CALM2, PFN1, and FLNA were found to be enriched in these pathways. Validation using enzyme-linked immunosorbent assay (ELISA) in a larger cohort confirmed the differential expression of CALM2, FLNA, and PFN1. Our findings suggest that CALM2, FLNA, and PFN1, along with their associated pathways, represent potential therapeutic targets for PHN.