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Abstract Predicting gene expression divergence is integral to understanding the emergence of new biological functions and associated traits. Whereas several sophisticated methods have been developed for this task, their applications are either limited to duplicate genes or require expression data from more than two species. Thus, here we present PredIcting eXpression dIvergence (PiXi), the first machine learning framework for predicting gene expression divergence between single-copy orthologs in two species. PiXi models gene expression evolution as an Ornstein-Uhlenbeck process, and overlays this model with multi-layer neural network (NN), random forest, and support vector machine architectures for making predictions. It outputs the predicted class “conserved” or “diverged” for each pair of orthologs, as well as their predicted expression optima in the two species. We show that PiXi has high power and accuracy in predicting gene expression divergence between single-copy orthologs, as well as high accuracy and precision in estimating their expression optima in the two species, across a wide range of evolutionary scenarios, with the globally best performance achieved by a multi-layer NN. Moreover, application of our best-performing PiXi predictor to empirical gene expression data from single-copy orthologs residing at different loci in two species of Drosophila reveals that approximately 23% underwent expression divergence after positional relocation. Further analysis shows that several of these “diverged” genes are involved in the electron transport chain of the mitochondrial membrane, suggesting that new chromatin environments may impact energy production in Drosophila. Thus, by providing a toolkit for predicting gene expression divergence between single-copy orthologs in two species, PiXi can shed light on the origins of novel phenotypes across diverse biological processes and study systems.