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Abstract Background Breast cancer is the first cause of death among Women. Chemoresistance is believed to be responsible for most of the mortalities, thus using new therapeutic strategies are needed. Autophagy has been shown as a critical player in cancer cells response to chemotherapeutic drugs such as doxorubicin. However, autophagy effect on cancer cell can be viewed as a pro-death or a pro-survival role. Thus, increase or decrease of this process in cells relative to its baseline can induce cancer cell death. Thus, we investigated if L-Lysine can increase doxorubicin effectiveness in combination therapy through autophagy modulation. Methods MDA-MB-231 and MDA-MB-468 were used as two breast cancer cell lines. Cells were treated with various concentrations of doxorubicin and L-Lysine. Cell viability was assessed using MTT assay 24 and 48h after treatment. ROS and NO level was examined and the expression of various autophagy and apoptosis related proteins/genes were evaluated with western blotting and real-time PCR respectively. Results L-Lysine increased cytotoxicity effect of doxorubicin in both MDA-MB-231 and MDA-MB-468 by autophagy enhancement. L-Lysine reduced cell viability and increased apoptosis in combination with doxorubicin. Real-time PCR analysis indicated that the combination of these two drugs resulted in increased autophagy as well as apoptosis-related genes. Moreover, reactive oxygen species (ROS) and nitric oxide (NO) production increased 30min after treatment with both drugs. However, the amount of these molecules decreased after 24h which can be results of autophagy induction. These results were further confirmed at protein levels of LC-3 and mTOR by western blotting. Conclusion Our findings indicated that L-Lysine can reduce the resistance to doxorubicin in triple negative breast cancer cells, MDA-MB-231 and MDA-MB-468. Therefore combination therapy with L-Lysine and doxorubicin could be consider an effective strategy in breast cancer therapy.