The use of plant extracts by cancer patients during chemotherapy poses potential risks, as they may reduce the effectiveness of treatment or interact negatively with chemotherapeutic drugs. There is a lack of comprehensive studies evaluating the effects of various Centaurea spp. plant extracts on chemotherapy outcomes, highlighting the need for caution and medical supervision. Therefore, the aim of this study was to evaluate the effects of five Centaurea spp. extracts in concentrations of 125 μg/ml and 250 μg/ml on the cytotoxicity induced by doxorubicin (DOX, 1 μM) in MCF-7 breast cancer cells and by bortezomib (BOR, 7 nM) in PC-3 prostate cancer cells. Selected cell lines were treated with drugs and extracts or combined for 48 h. Biological assays revealed that four out of five tested extracts abolished the cytotoxic effects of DOX and BOR. The extracts showed low antioxidant activity compared to Trolox, with no correlation to total compound content, indicating the abolition of the cytotoxic effect was not due to antioxidant activity. However, genotoxicity and DNA damage response studies showed a protective effect of the extract on the DNA of cancer cells and upregulation of DNA repair, which may underlie the reversal of the chemotherapy effect.