The SH2 domain-containing phosphatase 2 (SHP2) is a widely expressed protein tyrosine phosphatase, and it is proposed to act as an oncogenic protein. SHP2 is also engaged in drug resistance of a variety of cancers. However, the role of SHP2 in the proliferation and drug resistance of colon cancer cells remains elusive. In this work we determined the effect of SHP2 expression on colon cancer cell proliferation and resistance to oxaliplatin (L-OHP), a commonly used drug in the clinic. Our results show that knockdown of SHP2 decreased and overexpression of SHP2 increased the proliferation of SW480 cells, respectively. Knockdown of SHP2 increased, and overexpression of SHP2 decreased apoptosis of the cells. We selected oxaliplatin-resistant SW480(SW480/L-OHP) and HCT116(HCT116/L-OHP) cells and found that the SHP2 protein level was raised in these drug-resistant cells. The upregulated SHP2 contributed to oxaliplatin resistance of the cells, as knockdown of SHP2 decreased the IC of oxaliplatin and abated proliferation and survival of SW480/L-OHP and HCT116/L-OHP cells in the presence of oxaliplatin. Also, SW480/L-OHP and HCT116/L-OHP cells had increased phosphorylation of AKT and ERK. Inhibition of AKT, ERK, or SHP2 sensitized SW480/L-OHP and HCT116/L-OHP cells to oxaliplatin. Our results indicate that SHP2 contributes oxaliplatin resistance through AKT and ERK. These results also suggest that SHP2-targeting is a potential strategy for overcoming oxaliplatin resistance of colon cancer cells.