The study aimed to investigate the in vitro inhibitory activities of spiro N-propargylic β-enaminones, SPEs 1-31, against BCa cells, to perform in silico molecular docking studies to understand the nature of the interaction between the compounds and the ERα, PR, EGFR, and Her2, and to determine the ADMET and drug-likeness properties. Cytotoxic activity was investigated via MTT assay. DNA fragmentation was evaluated via ELISA assay. Cell cycle distributions were investigated by flow cytometry. Expression levels of Bcl-2, Bax, p21 and Cyclin D1 were measured by qRT-PCR and western blot analysis. Molecular docking was done using Autodock/vina software. ADMET analysis was calculated using the ADMETlab 2.0 tool. SPEs 1, 22, and 28 showed selective cytotoxic activity against all BCa cells with SI values >2. SPEs induced apoptosis and caused significant changes in Bcl-2 and Bax levels. The cell cycle was arrested at the S phase and levels of p21 and Cyclin D1 were induced in all BCa cells. Molecular docking analysis revealed that SPE1, SPE22, and SPE28 showed high binding affinities with ERα, PR, EGFR, and Her2. ADMET analysis revealed that SPEs are drug-like compounds as they obey the five rules of Lipinsky and are not toxic. Therefore, these potential anticancer compounds should be further validated by in vivo studies for their appropriate function in human health with a safety profile, and a comprehensive drug interaction study should be performed.