AbstractAntibodies are proteins working in our immune system with high affinity and specificity for target antigens, making them excellent tools for both biotherapeutic and bioengineering applications. The prediction of antibody affinity changes upon mutations ($${{\Delta \Delta {\mathrm{G}}}}_{\mathrm{binding}}$$ΔΔGbinding) is important for antibody engineering. Numerous computational methods have been proposed based on different approaches including molecular mechanics and machine learning. However, the accuracy by each individual predictor is not enough for efficient antibody development. In this study, we develop a new prediction method by combining multiple predictors based on machine learning. Our method was tested on the SiPMAB database, evaluating the Pearson’s correlation coefficient between predicted and experimental$${{\Delta \Delta {\mathrm{G}}}}_{\mathrm{binding}}$$ΔΔGbinding. Our method achieved higher accuracy (R = 0.69) than previous molecular mechanics or machine-learning based methods (R = 0.59) and the previous method using the average of multiple predictors (R = 0.64). Feature importance analysis indicated that the improved accuracy was obtained by combining predictors with different importance, which have different protocols for calculating energies and for generating mutant and unbound state structures. This study demonstrates that machine learning is a powerful framework for combining different approaches to predict antibody affinity changes.