Doxorubicin (DOX) is an effective chemotherapeutic drug, but induces serious adverse effects. The anti-inflammatory drug colchicine (COL) was found to inhibit inflammasome activity involved in DOX side effects. The purpose of this research to investigate COL impact when being added to DOX, if decrease side effects or enhances its anti-tumor efficacy. To this end, we used Ehrlich ascitic carcinoma (EAC)-bearing CD1 female mice and treated them with high and low doses of DOX (DOXhigh and DOXlow) in the presence or absence of COL. Mice were inoculated intraperitoneally with 0.25 × 106 EAC-cells/mouse and then treated with DOXhigh (2 mg/kg), DOXlow (1 mg/kg), COL (5 µmol/kg), DOXhigh/COL and DOXlow/COL. On day 8 of tumor injection, 50% of the mice were sacrificed to evaluate tumor volume, total tumor cell count, EAC cell apoptosis, cell cycle, hematological, and biochemical parameters, including liver and kidney function tests, oxidative stress (OS) markers, C-reactive protein (CRP), and interleukin 1-beta (IL-1β). The remaining 50% of mice were left to determine the survival of the groups. Co-treatment of COL with DOXhigh or DOXlow enhanced the overall antitumor effect of DOX as evidenced by an enhancement in the tumor parameters, an increase in EAC cell apoptosis, and induction of cell cycle arrest. Additionally, their co-treatment ameliorated DOX adverse effects as evidenced by an improvement in the measured markers. Conclusion: Combination of COL with DOXhigh or DOXlow enhanced the antitumor effect and decreased the adverse effects. This study opens a new avenue to their use in the clinical setting.