Keloids are a common dermal pathological disorder characterized by the excessive deposition of extracellular matrix components; however, the exact pathogenesis of the disease is still not clear. Studies increasingly suggest that microRNAs (miRNAs) can play a key role in the process of keloid scarring. In this study, the valuable miRNAs and target genes were screened and the interaction network was constructed. We also predicted target genes of reported miRNAs using TargetScan and miRTarBase software. Cytoscape 3.0.1 further showed the interaction network of miRNA and target genes. Among the various miRNAs involved in keloid pathogenesis, miRNA-21, miRNA-141-3p, miRNA-181a, and miRNA-205 were thought to up-regulate the proliferation and decrease apoptosis of keloid-derived fibroblasts through the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway. miRNA-637 and miRNA-1224 inhibited keloid fibroblasts proliferation and promoted apoptosis via the transforming growth factor (TGF)-beta 1/Smad3 signaling pathway. miRNA-21 was also involved in mitochondrial-mediated apoptosis and miRNA-31 targeted vascular endothelial growth factor (VEGF) signaling pathway. miRNA-199a may be one key factor in the cell cycle checkpoint signal pathway of keloid-derived fibroblasts. It was also found that miRNA-29a and miRNA-196a mediated collagen metabolism. These pivotal miRNAs and regulatory processes further improve the data on the epigenetic mechanisms of keloids and provide hope for the use of small molecules in the treatment of keloids.