The development of drug resistance in cancer cells had caused the treatment of cancer to be challenging. In this study, we suggest a potential treatment against chemo-drug resistant breast cancer cells. Curcumin, a bioactive compound extracted from Curcuma longa, was reported to be a potential drug to treat human cancer (Cao et al., 2022; Guney Eskiler et al., 2020; Li et al., 2014; Sun & Fang, 2021). The objective of the study was to investigate the cellular activities of Curcumin on the Estrogen receptor and proteins associated with BCL-2 family in chemo-drug resistant human breast cancer cells. MTT assay was used to determine the effects of Cisplatin, Curcumin, and Tamoxifen on the cell viability of chemo-drug resistant human breast cancer cells, MCF-7-CR (Cisplatin Resistant) and MDA-MB-231(Triple Negative) cells. Morphological changes of the cells after treatment were examined using phase-contrast microscopy followed by Clonogenic assay to identify viable cells. Western blot analysis was performed to analyse the protein expression of ERα, MOAP-1, and BAX. The results showed that the IC50 values of Curcumin were 207 μM and 100 μM for MCF-7 CR and MDA-MB-231 cells, respectively, suggesting MDA-MB-231 cells, which lack Estrogen Receptor, is more sensitive to Curcumin. The results were further support by Western blot analysis which showed that Curcumin down-regulated the expression of Estrogen receptor while up-regulated the expression of the pro-apoptotic proteins, MOAP-1 and BAX in MCF-7-CR cells, suggesting that Curcumin induces apoptotic cell death by inhibiting the expression of anti-apoptotic Estrogen receptor while promoting the expression of the pro-apoptotic MOAP-1 and BAX proteins.