This book constitutes the revised selected papers of the 21st Smoky Mountains Computational Sciences and Engineering Conference, SMC 2021, held in Oak Ridge, TN, USA*, in October 2021.The 33 full papers and 3 short papers presented were carefully reviewed and selected from a total of 88 submissions. The papers are organized in topical sections of computational applications: converged HPC and artificial intelligence; advanced computing applications: use cases that combine multiple aspects of data and modeling; advanced computing systems and software: connecting instruments from edge to supercomputers; deploying advanced computing platforms: on the road to a converged ecosystem; scientific data challenges. *The conference was held virtually due to the COVID-19 pandemic.