This book constitutes the proceedings of the 21stInternational Conference on Embedded Computer Systems: Architectures, Modeling, and Simulation, SAMOS 2021, which took place in July 2021. Due to COVID-19 pandemic the conference was held virtually.The 17 full papers presented in this volume were carefully reviewed and selected from 45 submissions. The papers are organized in topics as follows: simulation and design space exploration; the 3Cs - Cache, Cluster and Cloud; heterogeneous SoC; novel CPU architectures and applications; dataflow; innovative architectures and tools for security; next generation computing; insights from negative results.