Cancer is a broad term used to describe a large number of diseases characterized by uncontrolled cell proliferation that leads to tumor production. Cancer is associated with mutations in genes controlling proliferation and apoptosis, oxidative stress, fatty acid synthase (FAS) expression, and other mechanisms. Currently, most antineoplastic drugs have severe adverse effects and new effective and safe drugs are needed. This study aims to investigate the possible anticancer activity of rutin and orlistat which are both safely used clinically in humans against two breast cancer models (in vivo EAC and in vitro MCF7) and the pancreatic cancer cell line (PANC-1). Our results have shown that both rutin and orlistat exerted an in vivo anticancer activity as evidenced by the decrease in tumor volume, CEA level, cholesterol content, FAS, and the exerted antioxidant action (reduced MDA level and increased GSH content) and through histopathological examination. In addition, both were cytotoxic to MCF-7 and Panc-1 cell lines by promoting apoptosis. In conclusion, the anticancer activity of rutin and orlistat makes them promising candidates for cancer treatment alone or in combination with other anticancer drugs specially that they are used clinically with an acceptable safety profile.