Sustainability and circular economy enclose initiatives to achieve economic systems and industrial value chains by improving resource use, productivity, reuse, recycling, pollution prevention, and minimizing disposed material. However, shifting from the traditional linear economic production system to a circular economy is challenging. One of the most significant hurdles is the absence of sustainable end-of-life (EoL)/manufacturing loops for recycling and recovering material while minimizing negative impacts on human health and the environment. Overcoming these challenges is critical in returning materials to upstream life cycle stage facilities such as manufacturing. Chemical flow analysis (CFA), sustainability evaluation, and process systems engineering (PSE) can supply chemical products and processes performances from environmental, economic, material efficiency, energy footprint, and technology perspectives. These holistic evaluation techniques can improve productivity, source material reduction, reuse, recycling, and prevent and minimize releases and disposal rates. Therefore, this contribution offers a computational framework that covers CFA, sustainability assessment, and risk evaluation for quantifying the benefits and challenges of chemical circular economy routes versus conventional linear systems. Finally, this contribution shows promising techniques and challenges for employing CFA, sustainability evaluation, and PSE as multicriteria decision-making tools for designing a closed-loop chemical management infrastructure and transforming the US chemical industry sector from linear to circular.