The ten-volume set LNCS 12949 - 12958 constitutes the proceedings of the 21st International Conference on Computational Science and Its Applications, ICCSA 2021, which was held in Cagliari, Italy, during September 13 - 16, 2021. The event was organized in a hybrid mode due to the Covid-19 pandemic.The 466 full and 18 short papers presented in these proceedings were carefully reviewed and selected from 1588 submissions. The books cover such topics as multicore architectures, computational astrochemistry, mobile and wireless security, sensor networks, open source software, collaborative and social computing systems and tools, computational geometry, applied mathematics human computer interaction, software design engineering, and others. Part V of the set includes the the proceedings on the following workshops: International Workshop on Computational Geometry and Applications (CGA 2021); International Workshop on Collaborative Intelligence in Multimodal Applications (CIMA 2021); International Workshop on Computational Science and HPC (CSHPC 2021); International Workshop on Computational Optimization and Applications (COA 2021); International Workshop on Cities, Technologies and Planning (CTP 2021); International Workshop on Computational Astrochemistry (CompAstro 2021); International Workshop on Advanced Modeling E-Mobility in Urban Spaces (DEMOS 2021).The chapters "On Local Convergence of Stochastic Global Optimization Algorithms" and "Computing Binding Energies of Interstellar Molecules by Semiempirical Quantum Methods: Comparison between DFT and GFN2 on Crystalline Ice" are published open access under a CC BY license (Creative Commons Attribution 4.0 International License).