Colorectal carcinoma (CRC) is the 3rd most common cancer worldwide, thus development of novel therapeutic strategies is imperative. Herein potent, selective dose-dependent antitumor activity of horse spleen apoferritin encapsulated PbS quantum dots (AFt-PbS) against two human-derived colorectal carcinoma cell lines is reported (GI50∼ 70 μg mL-1). Following in vitro exposure to AFt-PbS, CRC cells fail to recover proliferative capacity, and undergo apoptosis triggered by the generation of reactive oxygen species (ROS). In stark contrast, the AFt-PbS nanocomposites do not affect the growth and cell cycle of non-tumor human microvessel endothelial HMEC-1 cells (GI50 > 500 μg mL-1). In vivo, AFt-PbS QDs are well tolerated by mice. Neither adverse health nor behavioral indicators were observed throughout the 15 day study. The photoluminescence of AFt-PbS combined with selective antitumor activity offer potential development of AFt-PbS for simultaneous non-invasive imaging and treatment of malignant tissue.