A multidisciplinary Safe-and-Sustainable-by-Design (SSbD) framework enabled synthesis of a non-toxic bisphenol-based polyester with attractive mechanical and thermal properties. We implemented a workflow that minimized synthetic efforts and associated chemical exposure by initial evaluation of endocrine disruptive effects for a library of bisphenols using an in silico model. This predictive evaluation resulted in the selection of a limited number of promising candidates that were synthesized from lignin-sourced reagents using renewable solvent and non-toxic catalysts. These candidates were evaluated for estrogenic activity by an in vitro toxicity assessment, which resulted in the selection of one non-estrogenic bisphenol that was successfully incorporated into a polyester matrix. As such, the present study demonstrates how the SSbD principles can guide the development of sustainable and safe materials with attractive properties for future applications in consumer products.