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 II of the set follows two generaltracks: geometric modeling, graphics and visualization; advanced and emerging applications. Further sections include the proceedings of the workshops: International Workshop on Advanced Transport Tools and Methods (A2TM 2021); International Workshop on Advances in Artificial Intelligence Learning Technologies: Blended Learning, STEM, Computational Thinking and Coding (AAILT 2021); International Workshop on Advancements in Applied Machine-learning and Data Analytics (AAMDA 2021). At the end of the book there is a block of short papers. The chapter "Spatial justice models: an exploratory analysis on fair distribution of opportunities" is published open access under a CC BY license (Creative Commons Attribution 4.0 International License).