This book constitutes the refereed proceedings of the 21st International Conference on Information Systems Security, ICISS 2025, held in Indore, India, during December 16–20, 2025.The 15 full papers and14 short papers included in this volume were carefully reviewed and selected from 93 submissions. They were organized in topical sections as follows: Access Control; AI for Security; Applied Cryptography; Cyber Security Case Study; Fraud Detection; Intrusion Detection; Malware Detection; Network Security; Privacy; and System Security.