New 5-aminosalicylamide-4-thiazolinone hybrids (27) were efficiently synthesized, characterized, and evaluated to explore their structure–activity relationship as anticancer agents. The antiproliferative activities of the new hybrids were evaluated against eight cancer cell lines using the sulforhodamine B assay. The most potent compound (24b) possessed high selectivity on the tested cell lines in the low micromolar range, with much lower effects on normal fibroblast cells (IC₅₀ > 50 µM). The cell lines derived from leukemia (Jurkat), cervix (HeLa), and colon (HCT116) cancers appeared to be the most sensitive, with IC₅₀ of 2 µM. 24b is the N-ethylamide derivative with p-dimethylaminobenzylidene at position 5 of the 4-thiazolinone moiety. Other N-substituents or arylidene derivatives showed lower activity. Hybrids with salicylamides showed lower activity than with methyl salicylate. The results clearly show that the modifications of the carboxy group and arylidene moiety greatly affect the activity. Investigating the possible molecular mechanisms of these hybrids revealed that they act through cell-cycle arrest and induction of apoptosis and epidermal growth factor receptor (EGFR) inhibition. Molecular docking studies rationalize the molecular interactions of 24b with EGFR. This work expands our knowledge of the structural requirements to improve the anticancer activity of 5-aminosalicylic-thiazolinone hybrids and pave the way toward multitarget anticancer salicylates.