We investigated the role of a disintegrin and metalloproteinase 17 (ADAM17) in chemo resistance, and to clarify the mechanism underlying reverse of L-OHP resistance by knockdown of ADAM17. CRC tissues with corresponding adjacent normal tissues were collected. The mRNA and protein expression of ADAM17 in tissues were detected by RT-qPCR, immunohistochemistry and Western blot. The prognostic impact of ADAM17 expression were then validated in TCGA database to confirm the results. Resistance to oxaliplatin was induced in HCT-8 (HCT-8/L-OHP) colorectal cancer cell line by exposing cell to increasing concentrations of L-OHP. MTT were used to evaluate the resistance to L-OHP. Subsequently, Knockdown of ADAM17 in HCT-8 and HCT-8/L-OHP cells to explore the mechanism through which ADAM17 shRNA reverses L-OHP resistance. Our result showed that ADAM17 was higher expression in the cancerous tissue and related to the chemosensitivity. Moreover, ADAM17 shRNA, AG1478 and LY294002 could inhibit cell proliferation, induce apoptosis and increase oxaliplatin sensitivity in HCT-8/L-OHP and parental colorectal cancer cell line, but nonsense shRNA did not show this effect. Western blot analysis further confirmed that EGFR/PI3K/AKT signaling pathway is involved in ADAM17 shRNA inhibiting proliferation and chemosensitivity of HCT-8/L-OHP and HCT-8 cells. The present study provides the evidence that downregulation of ADAM17 could increase the sensitivity to chemotherapy, inhibit cell proliferation, induce apoptosis, and reverse oxaliplatin resistance via suppression of the EGFR/PI3K/AKT signaling pathway in CRC.