This book constitutes the proceedings of the 13th International Symposium on Search-Based Software Engineering, SSBSE 2021, which was held in Bari, Italy, during October 11-12, 2021. The 9 full and 2 short papers included in this volume were carefully reviewed and selected from 19 submissions. The papers deal with novel ideas and applications of search-based software engineering, focusing on engineering challenges and the application of automated approaches and optimization techniques from AI and machine learning research.