The world faces an increasing need to phase out harmful chemicals and design sustainable alternatives across various consumer products and industrial applications. Alternatives assessment is an emerging field focusing on identifying viable solutions to substitute harmful chemicals. However, current methods fail to consider trade-offs from human and ecosystem exposures, and from impacts associated with chemical supply chains and product life cycles. To close this gap, we propose a life cycle based alternatives assessment (LCAA) framework for consistently integrating quantitative exposure and life cycle impact estimates in the substitution process. We start with a pre-screening based on function-related decision rules, followed by three progressive tiers from (1) rapid risk screening of all alternatives for the consumer use stage, to (2) an assessment of chemical supply chain impacts for selected alternatives with substantially different synthesis routes, and (3) an assessment of product life cycle impacts for alternatives leading to substantially different product life cycles. Each tier focuses on relevant impacts and uses streamlined assessment methods. While the initial risk screening will be sufficient for evaluating chemicals with similar supply chains, each additional tier helps further restricting the number of viable solutions, while avoiding unacceptable trade-offs. We test our LCAA framework in a proof-of-concept case study for identifying suitable alternatives to a harmful plasticizer in household flooring. Results show that the use stage dominates human health impacts across alternatives, supporting that a rapid risk screening is sufficient unless very different supply chains or a broader set of alternative materials or technologies is considered. Combined with currently used indicators for technical and economic performance, our LCAA framework is suitable for informing function-based substitution at the level of chemicals, materials and product applications to foster green and sustainable chemistry solutions.