Background/Aim: Multidrug resistance (MDR) is the leading cause of treatment failure in breast cancer patients treated with doxorubicin DOX). Previous indicated that some calcium channel blockers could reverse multidrug resistance. Therefore, we aimed to investigate the potential of nimodipine (a calcium channel blocker drug) in sensitizing breast cancer cells to DOX and elucidate the underlying molecular mechanisms. Methods: we examined the effects of DOX alone or in combination with nimodipine (NMD) on the viability of the MCF-7 cells using MTT assay, cell cycle by flow cytometry, and the expression of the MDR‐related gene (MDR1) and cell cycle/survival gene (Bcl‐2) and the pro-apoptotic gene (Bax) by quantitative reverse transcription polymerase chain reaction. Results: we found that adding NMD to DOX potentiated its antiproliferation effect. The value of the combination index (CI) of NMD/DOX was less than 1 indicating a synergistic effect. Combined DOX/NMD treatment also caused G1 arrest and potentiated apoptosis more than DOX‐single treatment. At the molecular levels, NMD/DOX treatment downregulated the mRNA of MDR1 and Bcl‐2; while upregulated the Bax gene compared with DOX alone. Conclusion: the results confirmed the potential of NMD in sensitizing Breast cancer to DOX by targeting MDR1 and suppressing the Bcl‐2 gene while upregulating the Bax gene. Additionally, NMD could be repurposed to reduce the therapeutic doses of DOX as indicated by the dose reduction index (DRI) and subsequently decrease its side effects (especially cardiotoxicity), along with decreasing the chemoresistance of breast cancer cells to DOX treatment.