This book constitutes the refereed proceedings of the 15th Annual International Conference on Combinatorial Optimization and Applications, COCOA 2021, which took place in Tianjin, China, during December 17-19, 2021. The 55 papers presented in this volume were carefully reviewed and selected from 122 submissions. They deal with combinatorial optimization and its applications in general, focusing on algorithms design, theoretical and experimental analysis, and applied research of general algorithmic interest.