Objective To investigate the effects of Matrine (Ma) on drug resistance of human colon cells to Oxaliplatin (Oxa) and potential mechanisms. Methods Cellular proliferation of SW480/Oxa cell line was analyzed by MTT. Cell apoptosis rate was analyzed by Flow Cytometer. Expression of glycoprotein (P-gp), MDR1, P-gp, JNK and phosphorylated c-Jun N-terminal kinas (p-JNK) was measured by qRT-PCR and Western blot. Results MTT results showed that cell proliferation in Oxa group was lower than that in NC group (t = 4.032, P = 0.049), while that was higher when compared with Ma+Oxa group (t = 4.132, P = 0.045). Flow cytometer suggested that apoptosis rate in Oxa group was increased compared with NC group (t = 4.342, P = 0.043), while that was decreased when compared with Ma+Oxa group (t = 4.342, P = 0.043). Expressions of P-gp and MDR1 in PPARy+Ma+Oxa group was downregulated when compared with PPARy+Oxa group (P < 0.05), but was upregulated compared with Oxa group (P < 0.05). QRT-PCR also suggested manifested similar alteration of expression of P-gp and MDR1 in SP600125+Ma+Oxa group comparing with those in SP600125+Oxa group (P < 0.05). Western blot showed that expressions of P-gp and p-JNK proteins in PPARy+Ma+Oxa group were lower than PPARy+Oxa group (P < 0.05).Conclusions Ma can reverse drug resistance of colorectal cancer to Oxa potentially via the JNK/SAPK signaling pathway.