In this study, a new series of N-(di or trimethoxyaryl)-5-arylisoxazole-3-carboxamide derivatives were synthesized and evaluated against human breast cancer cell lines including MCF-7, MDA-MB-231, and T-47D. Among the synthesized compounds, 5-(m-tolyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide (8f) showed significant cytotoxicity against all three cell lines comparing with etoposide as the reference drug. Also, Annexin V-FITC/propidium iodide and acridine orange/ethidium bromide staining assay were performed to validate apoptotic activity of compound 8f. The results confirmed induction of apoptosis at early stage.