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, blockchain, mobile and wireless security, sensor networks, open source software, collaborative and social computing systems and tools, cryptography, applied mathematics  human computer interaction, software design engineering, and others. Part IV of the set includes the papers on Urban and Regional Planning and the proceedings of the following workshops: ​International Workshop on Blockchain and Distributed Ledgers: Technologies and Applications (BDLTA 2021); International Workshop on Computational and Applied Mathematics (CAM 2021); International Workshop on Computational and Applied Statistics (CAS 2021); International Workshop on Computerized Evaluation of Economic Activities: Urban Spaces (CEEA 2021).