Cancer resistance to chemotherapy is a clinical dilemma that eventually leads to increased mortality. It is widely accepted that cancer stem cells (CSCs) have a pivotal role in the development of resistance. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown a promise to combat CSCs, thus, we addressed for the first time the effect of indomethacin on cisplatin (CDDP)-resistant murine breast cancer along with the relevant mechanisms. The murine mammary adenocarcinoma, Ehrlich ascites carcinoma (EAC) cells, were made resistant by exposure to CDDP and the surviving cells were then analyzed by flow cytometry for the breast CSCs markers (CD44+CD24-). CDDP heavily enriched the CSCs population which was subsequently injected into mice. After tumors development, mice were treated with CDDP, or indomethacin, or co-treated with both drugs, or left untreated. Upon termination of the treatment period, blood samples were collected to measure the percentage of SCa-1,CD4+, CD62L+, and CD117+. The tumors were excised and analyzed for the relative expression of drug resistance-mediating miRNAs (miR-7, miR-21, miR-22, and miR-145) in addition to histopathological examination. Indomethacin drastically diminished the tumorigenicity of CDDP-resistant cells along with enhancing its sensitivity to CDDP which were correlated with its manipulating effect on miRNAs expression. Besides, indomethacin expanded the pool of immune cells that impart antitumor response. Indomethacin through targeting CSCs may confer better outcome than conventional chemotherapeutics in the treatment of resistant breast cancer.