The in vivo toxicity to eukaryotes of nanosilver (AgNP) spheres and plates in two sizes each was assessed using the simple model organism Caenorhabditis elegans. For each shape, smaller AgNP size correlated with higher toxicity, as indicated by reduced larval growth. Smaller size also correlated with significant increases in silver uptake for silver nanospheres. Citrate coated silver spheres of 20 nm diameter induced an innate immune response that increased or held steady over 24 h, while regulation of genes involved in metal metabolism peaked at 4 h and subsequently decreased. For AgNP spheres, coating altered bioactivity, with a toxicity ranking of polyethylene glycol (PEG) > polyvinylpyrrolidone (PVP) ≅ branched polyethyleneimine (BPEI) > citrate, but silver uptake ranking of PEG > PVP > citrate > BPEI. Our findings in C. elegans correlate well with findings in rodents for AgNP size vs. uptake and toxicity, as well as for induction of immune effectors, while using methods that are faster and far less expensive, supporting the use of C. elegans as an alternative model for early toxicity screening.