Breast cancer is the most common type of cancer in women and the second leading cause of death. Trible-negative breast cancer (TNBC) accounts for about 10% of all breast cancer. Unlike other forms of breast cancer, TNBC does not express estrogen, progesterone, or HER2 receptors. These cancer cells instead employ mechanisms to escape the immune system. One such mechanism involves the upregulation of the expression of PD-L1, a ligand encoded by the CD274 gene. Because cancer cells tend to produce higher levels of PD-L1 compared to normal cells, therapies that inhibit PD-L1 may be helpful. Flavonoids, polyphenols found abundantly in fruits and vegetables, have already been shown to be effective antioxidants, anti-inflammatories, and anticancer. Cardamonin, an aromatic enone within the flavonoid family, has been shown to display an array of pharmacological activities. The objective of this work was to investigate the ability of Cardamonin in decreasing the expression of PD-L1 in MDA-MB-231 (Caucasian) and MDA-MB-468 (African American) TNBC cell lines which are genetically distinct. The methodology included cytotoxicity assays, human B7H1/PD-L1 ELISA, and Real Time-Polymerase Chain Reaction (RT-PCR) assays. The results obtained showed that cardamonin treatment caused a dose-dependent decrease in cell viability in both cell lines in concentrations ranging from 3.12 µM to 200µM. ELISA data showed low levels of PD-L1 expression in both cell lines. Furthermore, RT-PCR assays demonstrated that cardamonin downregulated PD-L1 expression in MDA-MB-231cells in the presence or absence of IFN-γ, showing a more effective effect after the cells were stimulated. In MDA-MB-468 cells, cardamonin had an opposite effect, upregulating the expression of PD-L1. The data show that cardamonin may alter the production of PD-L1 at the transcription level in MDA-MB-231 TNBC cells, but not in MDA-MB-468 cells, corroborating with literature showing differences in the tumor microenvironments between African Americans and non-African Americans. In conclusion, cardamonin may have the therapeutic potential to decrease the levels of PD-L1 in the tumor microenvironment combating the cancer cells’ effectiveness of evading the immune system.