The transition towards safer and more sustainable chemicals and materials requires the systematic integration of safety, environmental, social, economic, and performance considerations from the earliest stages of innovation. This work presents an integrated Safe-and-Sustainable-by-Design (SSbD) framework developed within the PLANETS EU project, aimed at supporting informed decision-making for the development of safer substitution alternatives. The proposed approach combines life-cycle thinking with a multi-dimensional assessment strategy, enabling the identification and evaluation of key sustainability and safety hotspots across the value chain. A structured, funnel-shaped methodology is applied, beginning with a scoping phase using the Early-Stage Responsible Innovation (ESRI) tool to define relevant SSbD dimensions, life-cycle stages, exposure pathways, and hazard endpoints. This is followed by in-depth assessment and prioritisation using sensitivity analysis, multi-objective optimisation, and multi-criteria decision analysis. The framework is demonstrated through three industrially relevant case studies—surfactants, flame retardants, and plasticizers—highlighting its applicability in guiding safer substitution and reducing unintended trade-offs. Results show that early identification of critical factors supports more efficient and transparent decision-making while aligning innovation with regulatory and sustainability goals. Overall, this work contributes to operationalising SSbD by providing a practical decision-support system that integrates diverse data streams and stakeholder perspectives, ultimately enabling the design of safer, more sustainable, and high-performing products.