Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure-activity relationship studies. <i>In vitro</i> antiproliferative activity indicated that compounds <b>F-3</b> and <b>F-4</b> dramatically inhibited the proliferation of Huh7 (IC<sub>50</sub> = 0.05 or 0.04 μM, respectively) and SK-Hep-1 (IC<sub>50</sub> = 0.07 or 0.06 μM, respectively) cells. Furthermore, compounds <b>F-3</b> and <b>F-4</b> could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds <b>F-3</b> and <b>F-4</b> could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound <b>F-4</b> (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound <b>F-4</b> has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.