Long-term exposure to arsenic has been linked to tumorigenesis in different organs and tissues, such as skin; however, the detailed mechanism remains unclear. In this present study, we integrated "omics" including microRNAome, proteomics and metabolomics to investigate the potential molecular mechanisms. Compared with non-malignant human keratinocytes (HaCaT), twenty-six miRNAs were significantly altered in arsenic-induced transformed cells. Among these miRNAs, the differential expression of six miRNAs was confirmed using Q-RT-PCR, representing potential oxidative stress genes. Two-dimensional gel electrophoresis (2D-PAGE) and mass spectrometry (MS) were performed to identify the differential expression of proteins in arsenic-induced transformed cells, and twelve proteins were significantly changed. Several proteins were associated with oxidative stress and carcinogenesis including heat shock protein beta-1 (HSPB1), peroxiredoxin-2 (PRDX2). Using ultra-performance liquid chromatography and Q-TOF mass spectrometry (UPLC/Q-TOF MS), 68 metabolites including glutathione, fumaric acid, citric acid, phenylalanine, and tyrosine, related to redox metabolism, glutathione metabolism, citrate cycle, met cycle, phenylalanine and tyrosine metabolism were identified and quantified. Taken together, these results indicated that arsenic-induced transformed cells exhibit alterations in miRNA, protein and metabolite profiles providing novel insights into arsenic-induced cell malignant transformation and identifying early potential biomarkers for cutaneous squamous cell carcinoma induced by arsenic.