Acute erythroleukemia (AEL) is acute myeloid leukemia characterized by malignant erythroid proliferation. AEL has a low survival rate, which has seriously threatened the health of older adults. Calothrixin B is a carbazole alkaloid isolated from the cyanobacteria Calothrix and exhibits anti-cancer activity. To discover more potential anti-erythroleukemia compounds, we used calothrixin B as the structural skeleton to synthesize a series of new compounds. Methods: In the cell culture model, we evaluated apoptosis and cell cycle arrest using MTT assay, flow cytometry analysis, JC-1 staining, Hoechst 33258 staining, and Western blot. Additionally, assessing the curative effect in the animal model included observation of the spleen, HE staining, flow cytometry analysis, and detection of serum biochemical indexes. Results: Among the Calothrixin B derivatives, H-107 had the best activity against leukemic cell lines. H-107 significantly inhibited the proliferation of HEL cells with an IC₅₀ value of 3.63 ± 0.33 μM. H-107 induced apoptosis of HEL cells by damaging mitochondria and activating the caspase cascade and arrested HEL cells in the G0/G1 phase. Furthermore, H-107 downregulated the protein levels Ras, p-Raf, p-MEK, p-ERK and c-Myc. Pretreatment with ERK inhibitor (U0126) increased H-107-induced apoptosis. Thus, H-107 inhibited the proliferation of HEL cells by the ERK /Ras/Raf/MEK signal pathways. Interestingly, H-107 promoted erythroid differentiation into the maturation of erythrocytes and effectively activated the immune cells in erythroleukemia mice. Conclusion: Overall, our findings suggest that H-107 can potentially be a novel chemotherapy for erythroleukemia.