To underscore the significance of thiazole and thiadiazole moieties in advancing cancer treatment and support researchers in drug design, we developed a novel series of 1,3,4-thiadiazole and 1,3-thiazole derivatives. These were synthesized by reacting 2-(naphthalen-1-ylmethylene)-N-phenylhydrazine-1-carbothioamide with hydrazonoyl halides and α-halo-compounds. Spectroscopic data and alternative syntheses confirmed the structures. The growth-inhibitory potential against HepG2-1 liver cancer cells was evaluated using the MTT assay, revealing compounds 5c and 15 with IC50 values of 0.53 ± 0.82 and 0.61 ± 0.72 μM, respectively, demonstrating promising anticancer activity than doxorubicin (IC50 = 0.72 ± 0.49 μM). Given the high attrition rate in drug development, computational approaches were employed to mitigate risks associated with poor pharmacokinetics and safety. Molecular docking analyses of the synthesized compounds illustrated binding interactions at enzymes' sites, consistent with in vitro studies, indicating potential as antitumor agents. In silico investigations affirmed the ADMET profile's favorable oral bioavailability properties for the synthesized compounds. These findings highlight the potential of the investigated ligands as promising candidates for further development as antitumor medicines.