This book constitutes the proceedings of the 21st International Conference on Mathematical Optimization Theory and Operations Research, MOTOR 2022, held in Petrozavodsk, Russia, in July 2022.  The 21 full papers presented together with 6 invited abstracts lectures and 2 tutorial abstracts in this volume were carefully reviewed and selected from 88 submissions. The conference focuses on the following topics: Mathematical programming, bi-level and global optimization, integer programming and combinatorial optimization, approximation algorithms with theoretical guarantees and approximation schemes, heuristics and meta-heuristics, game theory, optimal control, optimization in machine learning and data analysis, and their valuable applications in operations research and economics.