Breast cancer (BC) is the most widespread malignant tumor among women and is the fifth leading cause of cancer mortality. Surgery, radiation, chemotherapy, and immunotherapy are used in combination to treat breast cancer, depending on the stage and type of tumor. Chemo-resistance remains a serious clinical problem in BC management. Currently, the role of autophagy in cancer resistance has become an intense area of investigation. This study aimed to state the impact of c-MYC knockdown on autophagy induction in chemo-sensitive and chemo-resistant breast cancer cells. In order to accomplish the aim of this study, we used two distinct types of breast cancer cell lines. Estrogen sensitive MCF‐7 cells, cultured in the presence of tamoxifen (TAM), and a triple-negative MDA-MB 231cell line, cultured in media containing doxorubicin (DOX). Changes in cellular morphology were noticed to have a resistant phenotype at the end of seven passages. Fluorescence microscopy revealed that c-MYC knockdown stimulates autophagy induction in acutely treated MCF-7 cells, elevated in MDR/ MCF-7 cells, and was highest in c-MYC silenced MDR- MCF-7 cells. c-MYC knockdown in MDR-MDA-MB231cells had the strongest emission compared to MDR-negative control (NC) MDA-MB231 cells and acutely treated MDA-MB231cells in both tested groups. qPCR estimated elevation in autophagic-related tested gene in acute tamoxifen-treated c-MYC silenced MCF-7 cells, indicating higher autophagy induction. Repression of c-MYC in TAM resistance MCF-7 cells elevates the expression of all tested autophagy-related genes compared to NC cells. As for MDA-MB231 cells, qPCR estimated increased levels of all tested autophagic-related genes in acute doxorubicin treated cells, conversely, reduction of c-MYC decreased most autophagic related genes expression. Reduction of c-MYC in MDR/ MDA-MB231 cells elevated expression levels of all autophagic tested genes more than MDR/ MDA-MB231(NC) cells. In conclusion, c-MYC knockdown had different autophagic induction effects on breast cancer cells regarding their type in chemo-sensitive cells; it was found to be elevated in MCF-7 cells, while decreased in MDA-MB 231 cells. However, it elevates autophagy in chemo-resistant cells.