Background: Aloe-emodin is reported as a potential cancer therapeutic agent due to its inhibition of the proliferation, migration, and invasion of cancer cells. This study aimed to confirm the effects of aloe-emodin on the progression of melanoma and identify the underlying molecular mechanisms. Methods: The effects of aloe-emodin treatment (concentrations ranging from 0 to 25 mu g, 48 h) on proliferation, apoptosis, distribution of cell cycle, migration, and invasion were detected by performing Cell Counting Kit-8 (CCK-8) assay, colony formation assay, flow cytometry, wound healing assay, and Transwell invasion experiments. Rescue experiments were carried out by overexpression of I3-catenin to verify the role of I3-catenin in the inhibition of melanoma by aloe-emodin. The analysis was carried out at the animal level by constructing tumor-bearing nude mice model. Results: The results showed that aloe-emodin prominently reduced the proliferation, migration, and invasion of melanoma cells. Additionally, it was found that aloe-emodin significantly enhanced the cell apoptosis and induced G2 phase arrest of melanoma cells via enhancing the expressions of cleaved-caspase3, bax, and reducing cyclinD1, c-myc, and bcl-2. In addition, aloe-emodin could also inhibit Wnt3a levels, and promote GSK3-beta and beta-catenin phosphorylation. In vivo experiments also showed that overexpression of beta-catenin reversed the effects of aloe-emodin on tumor growth. Conclusions: In conclusion, our findings indicated that aloe-emodin might prominently inhibit the tumor growth and metastasis of melanoma via the Wnt/beta-catenin signaling pathway in vitro. Therefore, aloeemodin may serve as a potential drug for the clinical treatment of melanoma.