Schwann cells (SCs) proliferation is crucial for nerve regeneration following nerve injury. This study aims to investigate effects of interleukin-22 (IL-22) on SCs proliferation in vitro, as well as the corresponding mechanism. Rat SCs were treated with 100 ng/ml rat IL-22 for 48 h, and cell proliferation and apoptosis were detected using fluorescent staining and flow cytometry. After transcriptome sequencing, raw reads were filtered and mapped to reference genome rn5. Then, differentially expressed genes (DEGs) and long non-coding RNAs (DElncRNAs) between IL-22 and control groups were identified (tool: Cuffdiff). Functional and pathway enrichment analyses were performed (tool: GOFunction), and protein-protein interaction (PPI) network was constructed (tool: STRING and Cytoscape). Furthermore, Pearson's correlations between DEGs and DElncRNAs were analyzed, and regulatory network of DEGs, DElncRNAs, and transcription factors (TFs) was constructed. IL-22 significantly inhibited proliferation (p value < 0.05) and promoted apoptosis of Schwann cells. Totally, 932 DEGs and 118 DElncRNAs were identified, among which Ccl2 and Ccna2 were hub genes in PPI network. Up-regulated DEGs were enriched in apoptosis related terms, whereas down-regulated DEGs were enriched in proliferation related terms. DElncRNAs like NONRATT023505, NONRATG020400, and NONRATT022748 were correlated with multiple DEGs enriched in cell cycle and division. Moreover, up-regulated TFs Egr1, Cebpd, and Atf4 play crucial roles in regulatory network, and NONRATG020400-Cebpd-Ccl2, NONRATT023505/NONRATT022748-Atf4-Ccna2, and NONRATT022748-Egr1-Id1/Aldoc/Eno2/F3/Serpine1 regulatory pathways were identified in SCs after IL-22 treatment. IL-22 might influence SCs proliferation and apoptosis via regulating lncRNA-TF-gene pathways in SCs. However, more studies are required to confirm these results.