This book constitutes the refereed proceedings of the 12th International Conference on Decision and Game Theory for Security, GameSec 2021,held in October 2021. Due to COVID-19 pandemic the conference was held virtually. The 20 full papers presented were carefully reviewed and selected from 37 submissions. The papers focus on Theoretical Foundations in Equilibrium Computation; Machine Learning and Game Theory; Ransomware; Cyber-Physical Systems Security; Innovations in Attacks and Defenses.