By using mushroom polysaccharides–protein complexes (PSP) as the capping agent, size controllable and highly stable selenium nanoparticles (SeNPs) have been successfully created in a simple redox system of sodium selenite and ascorbic acid. SeNPs were capped with PSP through strong physical adsorption of hydroxyl groups of polysaccharides and imino groups of proteins on the surface of SeNPs. PSP surface decoration significantly enhanced the cellular uptake of SeNPs through endocytosis. Treatment with PSP–SeNPs significantly inhibited the growth of MCF-7 human breast cacinoma cells through induction of apoptosis with the involvement of PARP cleavage and caspase activation. Moreover, PSP–SeNPs not only significantly induced dose-dependent disruption of mitochondrial membrane potential in MCF-7 cells after 24 h treatment, but it also enhanced reactive oxygen species (ROS) generation as early as 15 min, indicating that ROS-mediated mitochondrial dysfunction may play an important role in PSP–SeNPs-induced apoptosis. Our results suggest that PSP–SeNPs may be a candidate for further evaluation as a chemopreventive agent for human cancers, and the strategy to use PSP as a surface decorator could be a highly efficient way to enhance the cellular uptake and anticancer efficacy of nanomaterials.