Natural polyphenolic compounds produced in plants exhibit many pharmacological effects including antioxidant, chemopreventive, and anticancer properties. This study was conducted to investigate the effect of cynarin (from artichokes, Cynara scolymus) and isoliquiritin (from licorice, Glycyrrhiza uralensis) on doxorubicin (positive control) cytotoxicity in different cell lines including normal (MCR-5 fibroblasts and H9c2 myoblasts) and cancer (colorectal HCT-116 and hepatocellular HEP-G2) cell lines. The cytotoxic effect of doxorubicin, isoliquiritin, and cynarin alone or in different combinations was studied on cancer cell lines as well as normal cell lines. The results obtained indicated that both cynarin and isoliquiritin enhance the cytotoxicity of doxorubicin. Both cynarin and isoliquiritin also reduce the cardiotoxicity of doxorubicin on normal cardiac cell lines. The combination of the three compounds (cynarin, isoliquiritin, and doxorubicin) decreases the cytotoxicity of doxorubicin, which may indicate the presence of interaction and/or antagonism effect between cynarin and isoliquiritin. Cynarin was found to enhance the growth of HCT-116 and HEP-G2. This might suggest avoiding the use of artichokes in subjects susceptible to these cancers. All results were evaluated using a statistical path and showed significant findings. The mechanism of enhanced doxorubicinís cytotoxicity by cynarin or isoliquiritin also requires further investigation to explain the increasing and/or the decreasing effect of these polyphenolic compounds on the cytotoxicity of doxorubicin. The current findings can suggest safe minimum doses for the two or three-element combinations of compounds in the context of clinical trials and practice.