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, mobile and wireless security, sensor networks, open source software, collaborative and social computing systems and tools, cryptography, human computer interaction, software design engineering, and others. Part I of the set follows two general tracks: computational methods, algorithms, and scientific applications; high performance computing and networks.