To further improve the anti-tumor activity of Harmine (HM), we took the hybridization approach and synthesized harmine derivatives-furoxan hybrids containing nitric oxide (NO) releasing parts by connecting NO donors with anti-tumor active fragments to harmine. Then, the synthesized compounds were evaluated for their in vitro cytotoxicity against five human cancer cell lines. Among them, compound 10 was found to have the strongest antiproliferative activity against HepG2 (IC<sub>50</sub> = 1.79 µM). In addition, compound 10 produced high levels of NO in vitro, verifying that the release of NO was closely correlated to the antiproliferative activity. In addition, Compound 10 also showed good plasma stability. Finally, we also preliminarily investigated the acute toxicity of compound 10 in mice and assessed the absorption of compound 10 by Caco-2 cell permeability assay. In brief, the remarkable biological characteristics of the new harmine derivatives-furoxan hybrids may make them promising candidates for human cancer intervention.