A new series of thiazolyl–pyrimidine hybrids (5a–g, 7, and 10a–e) was synthesized via the condensation of bromoacetyl dihydropyrimidinone with various thiosemicarbazones. The identity of the synthesized compounds was established using elemental analysis along with IR, ¹H NMR, ¹³C NMR, and mass spectrometry. Their antiproliferative potential was subsequently assessed against MCF-7 (breast) and HepG-2 (liver) cancer cell lines, with doxorubicin employed as the standard reference. Several derivatives showed potent cytotoxicity; notably, 5g, 5b, 5f, and 10e exhibited IC₅₀ values of 3–5 μM, comparable to doxorubicin. Structure–activity relationship (SAR) studies indicated that electron-donating para-substituents and heteroaryl/coumarinyl moieties enhanced activity, while bulky fused rings and halogen groups reduced it. Given the persistent burden of breast and liver cancers, and the critical role of epidermal growth factor receptor (EGFR) in tumor progression, selected hybrids (5a, 5b, 5f, 5g, 10d, and 10e) were further investigated in silico. Molecular docking revealed strong binding to the cancer receptor, supporting their potential as anticancer leads. ADMET predictions suggested favorable pharmacokinetic and safety profiles. Collectively, these findings identify thiazolyl–pyrimidine hybrids as promising scaffolds and apoptosis inducers for future breast and liver cancer therapy.