Additive and dominance effect QTL for grain yield and protein content display antagonistic pleiotropic effects, making genomic selection based on the index grain protein deviation a promising method to alleviate the negative correlation between these traits in wheat breeding. Grain yield and quality-related traits such as protein content and sedimentation volume are key traits in wheat breeding. In this study, we used a large population of 1604 hybrids and their 135 parental components to investigate the genetics and metabolomics underlying the negative relationship of grain yield and quality, and evaluated approaches for their joint improvement. We identified a total of nine trait-associated metabolites and show that prediction using genomic data alone resulted in the highest prediction ability for all traits. We dissected the genetic architecture of grain yield and quality-determining traits and show results of the first mapping of the derived trait grain protein deviation. Further, we provide a genetic analysis of the antagonistic relation of grain yield and protein content and dissect the mode of gene action (pleiotropy vs linkage) of identified QTL. Lastly, we demonstrate that the composition of the training set for genomic prediction is crucial when considering different quality classes in wheat breeding.