Limited cutaneous systemic sclerosis is one subtype of systemic sclerosis which is characterized by a prototypic multisystem fibrotic disorder. This study aimed to further investigate the pathological mechanism of limited cutaneous systemic sclerosis (lcSSc). The dataset GSE76807 generated from 10 lcSSc patients and five healthy controls was used. After the preprocessing of the original data, differentially expressed genes (DEGs) were identified and then performed functional analysis, protein-protein interaction (PPI) network and module analysis. Additionally, the transcription factors (TFs) and miRNAs which potentially regulating DEGs were identified and the co-regulatory network was constructed. Finally, DEGs targeted by current drugs were identified. Real-time quantitative PCR analyses of some DEGs in mice with lcSSc were performed. Total 203 up-regulated and 189 down-regulated DEGs were obtained. The up-regulated genes were enriched in protein interactions at the synapses neuronal system, NCAM1 interactions, and CREB phosphorylation through the activation of CaMKII, while, cilium assembly, and endothelial form of nitric oxide synthase (eNOS) activation were enriched by down-regulated genes. SCRT2 and RABEP1 regulated by miR-218 were hub nodes in the network. DRD4 and GRIN2D were the main drug targets. RABEP1 and SSB were found lowly expressed in mice model with lcSSc. Endothelial form of NOS activation would be suppressed, and the process of neuronal migration and outgrowth would be activated to participant in the pathological mechanism of lcSSc. © 2019 Wiley Periodicals, Inc.