Wound healing, a multifaceted process, often leads to chronic wounds when disrupted. Predominantly, research in this area has relied on in vitro or animal models, which potentially oversimplify the intricacies of human wound healing. This simplification could contribute to the current gap in effective clinical therapies and prognostic tools. Our study aims to deepen the understanding of human skin wound healing mechanisms at the temporal protein level. Utilizing labeled mass spectrometry, we quantified the proteome of full-thickness skin samples at both acute and late healing stages from legs of 14 healthy individuals. Our results revealed distinct proteomic profiles corresponding to different wound healing days, indicating a unique protein signature for each stage. Functional enrichment analysis identified key elements such as post-translational modifications, histone interaction networks, and proteins related to transcription and metabolism as pivotal in the early phases of healing. Additionally, a comparative analysis of protein and mRNA expression in similar sample types revealed only moderate correlation, suggesting that mRNA assessments alone might not fully capture the complexity of the healing process. This finding underscores the necessity for multi-omics approaches to comprehensively understand complex molecular mechanisms such as human skin wound healing.