New series of quinoline, pyrimido[4,5-b]quinoline, [1,2,3]triazino[4,5-b]quinoline, and [1,2,4]triazolo[2′,3′:3,4]pyrimido[6,5-b]quinoline analogs have been synthesized and characterized by analytical and spectrometrical methods (IR, 1H NMR, 13C NMR, MS). Fifteen of the newly synthesized compounds; namely, 3a, b, 4b, 6a, b, 10a–f, and 14a–d were evaluated for their in vitro antitumor activity at the National Cancer Institute (NCI) 60 cell lines panel assay. Compounds 4b and 10f are the most active members in this study, demonstrating significant broad spectrum antitumor activity against most of the tested sub-panel tumor cell lines. The detailed synthesis, spectroscopic, and biological data are described.