BackgroundHyperspectral imaging techniques have emerged as powerful tools for non-invasive investigation of artworks. This paper employs either reflectance imaging spectroscopy (RIS) or macroscopic X-ray fluorescence (MA-XRF) imaging in combination with macroscopic X-ray powder diffraction (MA-XRPD) for state-of-the-art chemical imaging of painted cultural heritage artefacts. While RIS can provide molecular information and MA-XRF can offer elemental distribution maps of paintings of high lateral resolution, the unique advantage of MA-XRPD lies in its ability to visualize the distributions of specific pigments and estimate in a quantitative manner the relative concentrations of the crystalline phases at the surface of artworks. However, MA-XRPD is more time-consuming and offers a lower lateral resolution than RIS and MA-XRF. ResultsThis study introduces a machine learning (ML) approach to obtain the distribution of specific compounds on the surface of artworks with a resolution that is comparable to that of RIS and MA-XRF data but with the compound specificity of MA-XRPD. The general aim is to expedite non-destructive artwork imaging analysis by fusing data from different imaging modalities via machine learning models. The effect of preprocessing techniques to enhance the predictive accuracy of the models is explored. The paper demonstrates the method's efficacy on a 16th-century illuminated manuscript, showcasing the feasibility of predicting compound-specific distribution maps. Three evaluation methods—visual examination of the predicted distribution, root mean square errors (RMSE), and feature permutation importance (FPI)—are employed to assess model performance. Fusing MA-XRF with MA-XRPD led to the best RMSE scores overall. However, fusing the RIS and MA-XRPD data blocks also yield very satisfactory and easily interpretable high-resolution compound maps. SignificanceWhile MA-XRPD allows for highly specific imaging of artworks, its time-consuming nature and limited resolution presents a bottleneck during non-invasive imaging of painted works of art. By integrating data from more time-efficient hyperspectral techniques such as MA-XRF and RIS, and employing machine learning, we expedite the process without compromising accuracy. The fusion process can also denoise the distribution maps, improving their readability for heritage professionals and art historical scholars.