Development of novel anti-cancer peptides requires a rapid screening process which can be accelerated by using appropriate in vitro tumor models. Breast carcinoma tissue is a three dimensional (3D) microenvironment, which contains a hypoxic center surrounded by dense proliferative tissue. Biochemical clues provided by such 3D cell mass can not be recapitulated in conventional 2D culture systems. In this experiment, we evaluate the efficacy of the sandalwood peptide on established in vitro 3D breast cancer model using invasive MDA-MB-231 cell line. The anti-proliferative effect of the peptide on 3D silk tumor model is monitored by alamar blue assay, with conventional 2D culture as control. Apoptotic cell morphology, DNA fragmentation assay and flow cytometry are investigated. Further investigations involve the combinatorial use of this peptide with doxorubicin; resulting decreased IC50 compared to the peptide alone. Overall, these findings indicate the role of sandalwood peptide as a promising anti-cancer therapeutics.