Abstract Motivation The prediction of reliable Drug–Target Interactions (DTIs) is a key task in computer-aided drug design and repurposing. Here, we present a new approach based on data fusion for DTI prediction built on top of the NXTfusion library, which generalizes the Matrix Factorization paradigm by extending it to the nonlinear inference over Entity–Relation graphs. Results We benchmarked our approach on five datasets and we compared our models against state-of-the-art methods. Our models outperform most of the existing methods and, simultaneously, retain the flexibility to predict both DTIs as binary classification and regression of the real-valued drug–target affinity, competing with models built explicitly for each task. Moreover, our findings suggest that the validation of DTI methods should be stricter than what has been proposed in some previous studies, focusing more on mimicking real-life DTI settings where predictions for previously unseen drugs, proteins, and drug–protein pairs are needed. These settings are exactly the context in which the benefit of integrating heterogeneous information with our Entity–Relation data fusion approach is the most evident. Availability and implementation All software and data are available at https://github.com/eugeniomazzone/CPI-NXTFusion and https://pypi.org/project/NXTfusion/.