This is an open access book. It gathers the second 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 advances relating to sustainable supply chain, remanufacturing and eco-design, and sustainability assessment. They also cover applications of digitalization and artificial intelligence to improve manufacturing efficiency and reducing its environmental impact, and in sustainable education and training. All in all, they offer extensive and timely information for both researchers and professionals in the field of manufacturing and business development.