Rotenone is a naturally occurring compound shown to exhibit antiproliferative activity against various cancer cell lines, indicating its potential as a lead anticancer agent. However, its toxicity against normal cells has prompted further investigation and chemical modifications. In this study, a library of carbonyl group-modified rotenone derivatives was synthesized and evaluated for their antiproliferative activities against MCF-7 breast cancer cells, A549 human lung carcinoma cells, and HCT116 human colorectal cancer cells using 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide (MTT) assay. The results showed several promising compounds that inhibited cell proliferation. Specifically, the oxime and alcohol rotenone derivatives exhibited antiproliferative activities against all 3 cancer cell lines, while the ethoxy, carbamate, and alkene derivatives are selective against MCF-7 (IC50 =5.72 μM), HCT116 (IC50 =8.86 μM), and A549 (IC50 =0.11 μM), respectively. SwissADME analysis showed that the physicochemical properties and drug-likeness of the synthesized rotenone derivatives were within the set limits, suggesting the favorable characteristics of these compounds for drug development. The findings obtained in this work highlight the potential of rotenone derivatives as promising chemotherapeutic candidates.