This is an open access book. It gathers the first volume of the proceedings of the 21st Global Conference on Sustainable Manufacturing, held on September 10–12, 2025, in Bologna, Italy. With a focus on Safe and Sustainable Value Creation by Design, the chapters in this book report on strategies towards the sustainable transformation of industry.  They cover applications of Lean Six Sigma, circularity evaluation, and methods for footprint calculations. They discuss new design approaches and advances in additive manufacturing and materials to improve safety and sustainability. All in all, they offer extensive and timely information for both researchers and professionals in the field of manufacturing and business development.