In this study, we aimed to understand how cytotoxic activity changes after the addition of a Schiff base and Ag(I) complex to the imidazo[2,1-b][1,3,4]thiadiazole nucleus, which has many biochemical applications. For this reason, a novel series of Salomo-type Schiff bases containing the imidazo[2,1-b][1,3,4]thiadiazole core (22-29) and their corresponding Ag(I) complexes (30-37) were synthesized and thoroughly characterized using FTIR, H-1 and C-13 NMR, ESI-MS, elemental analysis, and thermogravimetric analysis (TGA). The successful formation of imine linkages and silver coordination was confirmed by spectroscopic shifts and thermal decomposition patterns. The cytotoxic activities of the ligands and complexes were evaluated in vitro against A549 human lung carcinoma cells using the MTT assay. Among the tested compounds, ligands bearing electron-withdrawing groups such as Cl (e.g., ligand 29) exhibited the highest cytotoxicity, achieving complete cell death at 100 mu g/mL. In contrast, compounds containing electron-donating groups like CH3 (e.g., ligands 22, 25, and 27) showed moderate to low cytotoxic effects. Most silver(I) complexes displayed similar or slightly altered activity compared to their parent ligands, with complexation sometimes reducing cytotoxic potency, likely due to steric or solubility effects. The structure-activity relationship emphasizes the critical influence of electronic effects on anticancer potential. Furthermore, molecular docking simulations against the EGFR T790M mutant (PDB ID: 3UG2) revealed favorable binding profiles. Notably, ligand 29 showed the strongest in silico binding affinity, which strongly correlated with its in vitro cytotoxic performance. These findings support the further development of imidazothiadiazole-based Schiff bases, particularly those with electron-withdrawing substituents, as promising candidates in anticancer research.