Background Oral exposure to hexavalent chromium [Cr(VI)] can lead to gastrointestinal tumorigenesis in mice, and the mechanism is not yet clear. To predict health risk due to chemical exposure, data mining and computational toxicology analysis has become an important tool in toxicology research, which can help to elucidate mode of action (MOA) and identify key toxicity pathways. Objective This study aims to identify and evaluate key events in the MOA of oral Cr(VI) exposure. Methods Gene sets established from Comparative Toxicogenomics Database (CTD) and Gene Expression Omnibus (GEO) respectively were imported into Ingenuity® Pathway Analysis (IPA) software for pathway enrichment analysis and biological function analysis to identify potential key toxicity pathways of target organs/tissues toxicity of oral exposure to Cr(Ⅵ). Next, the weight of evidence (WOE) of the identified key toxicity pathways in the MOA of oral exposure to Cr(VI) was evaluated based on the modified Bradford Hill principle. Results A total of 54 pieces of literature related to oral Cr(VI) exposure were screened in CTD, among which 18 and 9 were related to liver and intestine with 125 and 272 corresponding genes, respectively. The pathway enrichment and biological function analysis results showed that liver and intestinal perturbation pathways were mainly related to cell stress and injury, cell cycle regulation, and apoptosis, indicating that Nrf2 pathway and AHR pathway might be the key toxicity pathways involved in the cytotoxic-mediated MOA. Meanwhile, the dose (≥170 mg·L⁻¹ sodium dichromate) and the time point (90 d) of the activation of Nrf2 pathway was similar to the emergence of crypt cell proliferation. It was proposed that Nrf2 pathway activation might be a key event for cytotoxic-mediated MOA of small intestinal tumors. The WOE results showed moderate validity of evidence in this hypothesis, with high validity of evidence for biological plausibility and dose-response manner. Conclusion Nrf2 pathway activation might be the key event in the cytotoxic-mediated MOA of small intestinal tumors induced by oral exposure to Cr(VI) via initiating or maintaining crypt cell proliferation.