This two-volume set, LNCS 12565 and 12566, constitutes the refereed proceedings of the 6th International Conference on Machine Learning, Optimization, and Data Science, LOD 2020, held in Siena, Italy, in July 2020. The total of 116 full papers presented in this two-volume post-conference proceedings set was carefully reviewed and selected from 209 submissions. These research articles were written by leading scientists in the fields of machine learning, artificial intelligence, reinforcement learning, computational optimization, and data science presenting a substantial array of ideas, technologies, algorithms, methods, and applications.