Oxaliplatin is a platinum-based chemotherapeutic drug that is effective and commonly used in the treatment of colorectal cancer (CRC). However, long-term use of oxaliplatin usually induces significant drug resistance. It is urgent to develop strategies to reverse the oxaliplatin resistance to CRC cells. In the present study, we established the model of oxaliplatin-resistant CRC cell lines (SW480/R and HT29/R) through continuous treatment of SW480 and HT29 cells with oxaliplatin. Results of qRT-PCR analysis showed that expression of miR-19a was significantly increased in SW480/R and HT29/R compared to their parental SW480 and HT29. However, combination treatment with anti-miR-19a, an antisense oligonucleotide of miR-19a, was found to resensitize SW480/R and HT29/R cells to oxaliplatin treatment. In the mechanism research, we found that anti-miR-19a increased the expression of PTEN and thus inhibited the phosphorylation of PI3K and AKT in SW480/R and HT29/R cells. As a result, mitochondrial apoptosis induced by oxaliplatin was expanded. We demonstrated that PTEN was the target of miR-19a and inhibition of miR-19a partially reversed the resistance of colorectal cancer to oxaliplatin via PTEN/PI3K/AKT pathway.