In this paper, a novel series of β-carboline-fused imidazolium derivatives (3a–3v) were designed and synthesized based on the structures of fascaplysin and our reported novel compound HMD-272 (9-(3-phenylpropyl)-2-benzyl-β-carbolinium bromide). Evaluation of the cytotoxicity of 3a–3v was conducted using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in lung carcinoma (A549), gastric carcinoma (BGC-823), murine colon carcinoma (CT-26), liver carcinoma (Bel-7402), and breast carcinoma (MCF-7) cell lines. The results demonstrated that the majority of the target compounds showed excellent activity against one or more cancer cell lines, and the compounds 3i, 3j, 3m, 3p, 3u, and 3v exhibited the highest cytotoxic activities (IC₅₀ < 10 μM) against the tested tumor cell lines. Preliminary investigations on the mechanisms of action revealed that compound 3v could dramatically inhibit EA.HY926 cell tube formation in a dose-dependent manner. Further investigation of the preliminary mechanism of action demonstrated that compound 3v had clear angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay. Moreover, a molecular docking study was performed in order to understand the binding pattern of compound 3v into the VEGFR2 active site. Docking results attributed the potent VEGFR2 inhibitory effect of the compound to its binding to the key amino acids in the active site (i.e., Ile892, Leu889, and Asp1046), as well as its hydrophobic interaction with the receptor hydrophobic pocket.