<p>Ribociclib (Ribo) and Abemaciclib (Abe) are new-generation CDK inhibitors approved for use in breast cancer treatment. They bind to CDK4/6 and inhibit the phosphorylation of retinoblastoma (RB) protein. Since it has high selectivity compared to other CDK inhibitors, their clinical use is quite common. It has been reported to significantly increase progression-free survival when used in combination with letrozole or fulvestrant. However, this combination has serious side effects. Bioactive compounds of plant origin come to the forefront in research to reduce drug side effects. Ferulic acid (FA) has high levels of anti-microbial and antioxidant activity, as well as pro-apoptotic, anti-metastatic, anti-inflammatory, and cell cycle arrest in cancer cells. In this study, we planned to evaluate the effects of FA in combination with Ribo and/or Abe in breast cancer. We observed that synergistic cytotoxic combinations of FA with Ribo and/or Abe triggered apoptosis in breast cancer cells due to increased expression of apoptosis-related genes, increased expression of ER stress-related genes, deregulated mitochondrial membrane potential, decreased cell proliferation, increased oxidative stress index and lipid peroxidation. Some molecular mechanisms were elucidated by revealing the synergistic effect of FA combined with Ribo and/or Abe in both HR positive and HR negative breast cancer and its possible toxicity or protection on normal breast cells. The present findings suggest that FA is a viable candidate for adjuvant or neoadjuvant treatment in combination with Ribo and/or Abe, as an alternative to Letrozole or Fulvestrant, which have been associated with significant adverse effects in clinical settings.</p>