Objective: To investigate anti-multidrug resistance (MDR) activity and safety of the bioactive fraction (CL11) from Codiaeum luzonicum crude leaf extract. Methods: Cytotoxic activity of CL11 against MDR and non- resistant colon cancer cells was assessed using MTT assay. Mode of cell death was investigated by annexin V-propidium iodide staining, TUNEL, and JC-1 assays. To examine mechanism of action, the effect on the expression and function of the MDR-implicated protein P-glycoprotein was tested using Western blotting and calcein assay, respectively. Results: CL11 had an EC 50 of 0.18, 1.03 and 38.52 μg/mL against HCT-15, HCT-15/Dox and HCT116, respectively. Cytotoxicity was mediated by inhibition of P-glycoprotein function and expression. The mode of cell death involved mitochondrial membrane depolarization and was mostly non-apoptotic at EC 50 concentrations against HCT-15 and HCT-15/Dox. Conclusions: Fraction CL11 of Codiaeum luzonicum induces non- apoptotic cell death in MDR cancer cells by overcoming MDR through inhibition of P-glycoprotein expression and function.