Silver nanoparticles (AgNPs) are important and widely used antimicrobials and nanodrug carriers. The increased use of AgNPs in consumer products has raised concerns about nanosafety; for instance, AgNPs may be inhaled and translocate to the brain via olfactory neural stem cells/progenitors. While the biological effects of nanoparticle size have been widely investigated, there are little data on the effects of particle shape on cellular phenotype. Therefore, here we investigated the interactions between AgNP spheres, rods, cubes, and triangles and human plasma proteins and their effects on the viability of NE-4C neural stem cells. Nanoparticles were synthesized by wet chemistry methods and characterized by UV-vis spectroscopy, dynamic light scattering, zeta potential measurement, transmission electron microscopy, nanoparticle tracking analysis, and differential centrifugal sedimentation. NE-4C cell viability was assessed using the MTT reduction assay, and the cellular uptake of differently shaped nanoparticles was monitored by electron microscopy. All 50 nm (in at least one dimension) AgNPs exerted toxic effects, with rods and cubes displaying greater toxicity than spheres and triangles. These cellular and physicochemical results indicate that edges on the AgNPs increase toxicity, presumably due to enhanced ion dissolution from the edges.