Aggregation of amyloid‐β peptide 1–42 (Aβ42) initiates the onset of Alzheimer's disease (AD), and all the drugs designed to attenuate AD have failed in clinical trials. Emodin reduces levels of β‐amyloid, tau aggregation, oxidative stress, and inflammatory response, demonstrating AD therapeutic potential, whereas its effect on the accumulation of the amyloid‐β protein is not well understood. In this work, we investigated emodin activity on Aβ aggregation using a range of biochemical, biophysical, and cell‐based approaches. We provide evidence to suggest that emodin blocks Aβ42 fibrillogenesis and Aβ‐induced cytotoxicity, displaying a greater effect than that of curcumin. Through adopting three short peptides (Aβ1‐16, Aβ17‐33, and Aβ28‐42), it was proven that emodin interacts with the Leu17‐Gly33 sequence. Furthermore, our findings indicated that Val18 and Phe19 in Aβ42 are the target residues with which emodin interacts according amino acid mutation experiments. When fed to 8‐month‐old B6C3‐Tg mice for 2 months, high‐dose emodin ameliorates cognitive impairment by 60%–70%. Pathological results revealed that levels of Aβ deposition in the brains of AD mice treated with a high dose of emodin decreased by 50%–70%. Therefore, our study indicates that emodin may represent a promising drug for AD treatment. We find emodin inhibits Aβ42 aggregation: Emodin blocks Aβ42 fibrillogenesis and Aβ‐induced cytotoxicity through interacting with Val18 and Phe19. High‐dose emodin greatly ameliorates cognitive impairment and the levels of cerebral Aβ deposition in Alzheimer's disease mice. Therefore, our study indicates that emodin may represent a promising drug for the treatment of Alzheimer's disease.