Engineered nanomaterials (ENMs) and ENM-enabled products have emerged as potentially high-performance replacements to conventional materials and chemicals. As such, there is an urgent need to incorporate environmental and human health objectives into ENM selection and design processes. Here, an adapted framework based on the Ashby material selection strategy is presented as an enhanced selection and design process, which includes functional performance as well as environmental and human health considerations. The utility of this framework is demonstrated through two case studies, the design and selection of antimicrobial substances and conductive polymers, including ENMs, ENM-enabled products and their alternatives. Further, these case studies consider both the comparative efficacy and impacts at two scales: (i) a broad scale, where chemical/material classes are readily compared for primary decision-making, and (ii) within a chemical/material class, where physicochemical properties are manipulated to tailor the desired performance and environmental impact profile. Development and implementation of this framework can inform decision-making for the implementation of ENMs to facilitate promising applications and prevent unintended consequences.