Peripheral nerve degeneration (PND) regulated by Schwann cells in a hydrogen sulfide (H2S)-pathway-dependent manner is well known, but the underlying molecular properties of Schwann cells during PND are unclear. We investigated H2S signaling in in vitro- and ex vivo-dedifferentiated Schwann cells as unipotent stem cells by using global proteomics (LC-MS) and transcriptomics (whole-genome and small RNA-sequencing [RNA-seq]) methods. The multi-omics analyses identified several genes and proteins related to oxidative stress, such as Sod1, Gnao1, Stx4, Hmox2, Srxn1, and Edn1. The responses to oxidative stress were transcriptionally regulated by several transcription factors, such as Atf3, Fos, Rela, and Smad2. In a functional enrichment analysis, cell cycle, oxidative stress and lipid/cholesterol metabolism were enriched, implicating H2S signaling in Schwann cell dedifferentiation, proliferation, and myelination. The H2S signaling pathway affect oxidative stress, lipid metabolism, and the cell cycle in Schwann cells during PND. Therefore, regulation of the H2S signaling pathway could reinforce the stem cell properties of Schwann cells and prevent their demyelination, dedifferentiation, and proliferation during PND.