Background: Triple-negative breast cancer (TNBC) has a poor prognosis and limited targeted therapies, with anthracyclines being key treatments. However, many patients show reduced responsiveness to these treatments, affecting their outcomes. Arachidonic acid metabolites, specifically epoxyeicosatrienoic acids (EETs) produced by cytochrome P450 (CYP) epoxygenase enzymes, have been implicated in TNBC progression. However, limited data exist on the role of CYP epoxygenase gene expression in the responsiveness of anthracycline-based therapy in TNBC. Thus, we aimed to test the contribution of these CYPs in anthracycline responsiveness among patients with TNBC and to explore whether inhibition of CYP epoxygenase can potentiate the anti-cancer activity of anthracyclines. Methods: Our study used the KM-plotter database to retrieve and extract patients’ data with TNBC. The patients were assigned to two cohorts: responders or less-responders to anthracycline based on relapse-free survival. Additionally, the effects of the CYP epoxygenase inhibitor MSPPOH in combination with doxorubicin were evaluated in the TNBC cell line. Results: The present study shows that TNBC patients with lower responsiveness to anthracycline-based therapy exhibited higher levels of CYP2C8, CYP2C9, and CYP2C19. We also found that these CYP2Cs could be potential biomarkers for predicting anthracycline responsiveness. Using human TNBC cells, we show that a selective CYP2C epoxygenase inhibitor, MSPPOH, significantly potentiates the anti-cancer effect of anthracycline. Conclusions: Collectively, this study provides preliminary evidence that CYP2C epoxygenase is involved in the therapeutic response to anthracyclines in TNBC, suggesting that these enzymes may serve as predictive biomarkers. However, given the limitations of using a public database and a single TNBC cell line, continued validation within larger, independent patient cohorts is needed.