In the context of the EU Chemicals Strategy for Sustainability toward a Toxic-free Environment, and in the aim to facilitate Safe-and-Sustainable-by-Design (SSbD) development of new materials and products, the EU-funded project HARMLESS built a Decision Support System (DSS) to support innovators in SSbD assessments of products at early design stages. The HARMLESS DSS is tailored to enable Advanced Materials (AdMa) screening, using a combination of New Approach Methodologies and guided by Integrated Approaches to Testing and Assessment. Three online tools for SSbD screenings are developed and tested on case study materials, namely: Advanced Materials Earliest Assessment; Warning flags, design Advice, Screening Priorities; and Alternative SSbD Inspector. The following case studies are assessed: oxide perovskites for automotive catalysts, imogolites for agricultural solutions, aerogel mats for facade insulation, and colloidal silica for paint formulations. The case study materials are provided by both large and small enterprises, they represent diverse industry sectors and different stages in the value chain. Results show the DSS ability to guide innovators in developing SSbD AdMa, by facilitating the assessment of most SSbD dimensions and visualizing the results in a comprehensive, yet detailed way, enabling their own balancing of SSbD benefits and trade-offs.