This book constitutes the refereed proceedings of the 16th International Conference on Learning and Intelligent Optimization, LION 16, which took place in Milos Island, Greece, in June 2022. The 36 full papers and 3 short papers presented in this volume were carefully reviewed and selected from 60 submissions. LION deals with automatic solver configuration, parallel methods, intelligent optimization, nature-inspired algorithms, hard combinatorial optimization problems, DC learning, computational intelligence, and others. The contributions were organized in topical sections as follows: Invited Papers; Contributed Papers.
