In connection with our continuous efforts to generate new derivatives from lead compounds isolated from traditional medicinal plants, a series of aloe-emodin derivatives (6a–6e) were synthesized and assessed for their potential anticancer activity against a panel of cancer cell lines. The results showed that most of the derivatives are more active than the aloe-emodin and particularly, 6b and 6e manifested potent activity with IC₅₀ values of 1.32 & 1.6 μM and 0.99 & 2.68 μM against MDA-MB-231 and MCF-7 cells, respectively. Moreover, 6b and 6e induce early and late apoptosis as well as arrest the cell cycle at the G2/M phase in MDA-MB-231 cells. In conclusion, the results confirmed that the aloe-emodin derivatives could be a potential drug candidate for better treatment of breast cancer.