Novel engineered nanomaterials (ENMs) are being introduced into the market rapidly with little understanding of their potential toxicity. Each ENM is a complex combination of diverse sizes, surface chemistries, crystallinity, and metal impurities. Variability in physicochemical properties is poorly understood but is critically important in revealing adverse effects of ENMs. A need also exists for discovering broad relationships between variations in these physicochemical parameters and toxicological endpoints of interest. Biological oxidative damage (BOD) has been recognized as a key mechanism of nanotoxicity. An assortment of 138 ENMs representing major classes are evaluated for BOD elicited (net decrease in the antioxidant capacity of ENM-exposed human blood serum, as compare to unexposed serum) using the ‘Ferric Reducing Ability of Serum’ (FRAS) assay. This robust and high-throughput approach has the ability to determine the co-effects which multiple physicochemical characteristics impart on oxidative potential, and subsequently to identify and quantify the influence of individual factors. FRAS BOD approach demonstrated the potential for preliminary evaluation of potential toxicity of ENMs, mapping the within- and between-class variability of ENMs, ranking the potential toxicity by material class, and prioritizing the ENMs for further toxicity evaluation and risk assessment.