Diseases can be caused by molecular perturbations that induce specific changes in regulatory interactions and their coordinated expression, also referred to as network rewiring. However, the detection of complex changes in regulatory connections remains a challenging task and would benefit from the development of novel non-parametric approaches. We developed a new ensemble method called BoostDiff (boosted differential regression trees) to infer a differential network discriminating between two conditions. BoostDiff builds an adaptively boosted (AdaBoost) ensemble of differential trees with respect to a target condition. To build the differential trees, we propose differential variance improvement as a novel splitting criterion. Variable importance measures derived from the resulting models are used to reflect changes in gene expression predictability and to build the output differential networks. BoostDiff outperforms existing differential network methods on simulated data evaluated in two different complexity settings. We then demonstrate the power of our approach when applied to real transcriptomics data in COVID-19 and Crohn’s disease. BoostDiff identifies context-specific networks that are enriched with genes of known disease-relevant pathways and complements standard differential expression analyses. BoostDiff is available at https://github.com/gihannagalindez/boostdiff_inference.