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Breast cancer is currently the most commonlydiagnosed cancer, with 287,850 new cases estimated for 2022 asreported by the American Cancer Society. Therefore, finding aneffective treatment for this disease is imperative. Chalcones are α,β-unsaturated systems found in nature. These compounds haveshown a wide array of biological activities, making them popularsynthetic targets. Chalcones consist of two aromatic substituentsconnected by an enone bridge; this arrangement allows for a largenumber of derivatives. Given the biological relevance of thesecompounds, novel ferrocene-heterocycle-containing chalcones weresynthesized and characterized based on a hybrid drug designapproach. These heterocycles included thiophene, pyrimidine,thiazolyl, and indole groups. Fourteen novel heterocyclic ferrocenyl chalcones were synthesized and characterized. Herein, we alsoreport their cytotoxicity against triple-negative breast cancer cell lines MDA-MB-231 and 4T1 and the noncancer lung cell lineMRC-5. System 3 ferrocenyl chalcones displayed superior anticancer properties compared to their system 1 analogues. System 3chalcones bearing five-membered heterocyclic substituents (thiophene, pyrazole, pyrrole, and pyrimidine) were the most activetoward the MDA-MB-231 cancer cell line with IC50 values from 6.59 to 12.51 μM. Cytotoxicity of the evaluated compounds in the4T1 cell line exhibited IC50 values from 13.23 to 213.7 μM. System 3 pyrazole chalcone had consistent toxicity toward both cell lines(IC50 ∼ 13 μM) as well as promising selectivity relative to the noncancer MRC-5 control. Antioxidant activity was also evaluated,where, contrary to anticancer capabilities, system 1 ferrocenyl chalcones were superior to their system 3 analogues. Antioxidantactivity comparable to that of ascorbic acid was observed for thiophene-bearing ferrocenyl chalcone with EC50 = 31 μM.