Objective: The study aimed to study the effect of histone methyltransferase KDM5c (Lysine(K)-specific demethylase 5C) on drug resistance in colon cancer cells. Methods: KDM5c expression interference was performed using empty plasmids, SMCV-dGFP-KDM5c plasmids and siControl, siKDM5c transfected human colon cancer HCT-8, RKO cell lines, and then grouped into NC, KDM5c-OE, siControl, siKDM5c groups. 0.625 mu g/ml, 1.25 mu g/ml, 2.5 mu g/ml, 5 mu g/ml, 10 mu g/ml, and 20 mu g/ml oxaliplatin (L-OHP), and 0.25 mmol/ml, 0.5 mmol/ml, 1 mmol/ml, 2 mmol /ml, 5 mmol/ml, and 10 mmol/ml irinotecan (CPT-11) were dosed in all colon cancer cell groups. The MTT assay was used to detect growth inhibition of differentially-expressed KDM5c colon cancer cells, for which L-OHP or CPT-11 were added. ABCC1 expression in qPCR and WB was detected in all four cell groups. The H3K4me3 peak distribution in the TSS region of the ABCC1 gene was detected with the Encode database. CHIP-qPCR was used to detect the location of the H3K4me3 peak and KDM5c binding to TSS region DNA fragments of the ABCC1 gene. Results: KDM5c expression upregulation in colon cancer cells had significantly reduced L-OHP and CPT-111/2 inhibitory concentrations (IC50 s) and decreased the ABCC1mRNA and protein expression. The IC50 s of L-OHP and CPT-11 were significantly increased in colon cancer cells with downregulated KDM5c expression. And, ABCC1 mRNA and protein expression increased (P < 0.05). The Encode database suggested that the H3K4me3 peak was located in the TSS region of the ABCC1 gene. CHIP-qPCR indicated that both H3K4me3 and KDM5c act on the TSS region of the ABCC1 gene and have the same site of action. Conclusions: KDM5c might downregulate ABCC1 expression by demethylating the ABCC1 H3K4me3 in the TSS region, which can promote multidrug resistance, such that inhibiting KDM5c could decrease multidrug cancer cell resistance.