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A new series of 5-(4-chlorophenyl)-1,3,4-thiadiazole-based compounds featuring pyridinium (<b>3</b>), substituted piperazines (<b>4a–g</b>), benzyl piperidine (<b>4i</b>), and aryl aminothiazoles (<b>5a–e</b>) heterocycles were synthesized. Evaluation of the cytotoxicity potential of the new compounds against MCF-7 and HepG2 cancer cell lines indicated that compounds <b>4e</b> and <b>4i</b> displayed the highest activity toward the tested cancer cells. A selectivity study demonstrated the high selective cytotoxicity of <b>4e</b> and <b>4i</b> towards cancerous cells over normal mammalian Vero cells. Cell cycle analysis revealed that treatment with either compound <b>4e</b> or <b>4i</b> induced cell cycle arrest at the S and G2/M phases in HepG2 and MCF-7 cells, respectively. Moreover, the significant increase in the Bax/Bcl-2 ratio and caspase 9 levels in HepG2 and MCF-7 cells treated with either <b>4e</b> or <b>4i</b> indicated that their cytotoxic effect is attributed to the ability to induce apoptotic cell death. Finally, an in vivo radioactive tracing study of compound <b>4i</b> proved its targeting ability to sarcoma cells in a tumor-bearing mice model.