Diffusion-weighted magnetic resonance imaging (DW-MRI) is a non-invasive technique that is sensitive to microstructural geometry in neural tissue and is useful for the detection of neuropathology in research and clinical settings. Tensor-valued diffusion encoding schemes (b-tensor) have been developed to enrich the microstructural data that can be obtained through DW-MRI. These advanced methods have proven to be more specific to microstructural properties than conventional DW-MRI acquisitions. Additionally, machine learning methods are particularly useful for the study of multidimensional data sets. In this work, we have tested the reach of b-tensor encoding data analyses with machine learning in different histopathological scenarios. We achieved this in three steps: 1) We induced different levels of white matter damage in rodent optic nerves. 2) We obtainedex vivoDW-MRI data with b-tensor encoding schemes and calculated quantitative metrics using Q-space trajectory imaging. 3) We used a machine learning model to identify the main contributing features and built a voxel-wise probabilistic classification map of histological damage. Our results show that this model is sensitive to characteristics of microstructural damage. In conclusion, b-tensor encoded DW-MRI data analyzed with machine learning methods, have the potential to be further developed for the detection of histopathology and neurodegeneration.