The present study was aimed at evaluating the effect of doxorubicin (Dox) loaded nanocrystals starch in human breast cancer MCF7 cells. A model for breast cancer, MCF7 cells, were treated with Dox loaded in S (native starch), NS (starch nanocrystal), ANS (acetylated starch nanocrystal) extracted from Oryza glaberrima Steud and compared with Dox (diluted in water). MTT assay, Hoechst33342, H2DCFDA, Live Death, and Rhodamine123 staining, and Western Blot were used to detect different signaling protein expressions and apoptosis. Hoechst33342 staining showed cellular apoptosis of MCF7 after treating with DOX loaded S, NS, ANS or Dox alone. Intracellular ROS levels, p53 and Bax/ Bcl2 expressions, and decrease in mitochondrial membrane potential were also higher in MCF7 cells treated with Dox loaded S, NS, ANS or Dox alone. To ensure Dox loaded S, NS or ANS did not cause any cellular damages to normal cells, HEK-293 kidney cells were used as control. Dox loaded S, NS, or ANS were as effective formulations as Dox alone to decrease progression and metastasis of breast cancer in MCF7 cells. This study provides a novel approach for further investigation since Dox loaded starch nanocrystals are effective and can prevent side effects of cardiotoxicity when using Dox alone.