Background: Tissues are three-dimensional (3D). However, current histopathology only allows 2D and single-marker tissue views. Methods: We utilized tissue clearing, supramolecular histochemistry, light-sheet microscopy, and image processing algorithms to compile an end-to-end multi-modality pipeline for 3D digital pathology and oncology diagnostics development. Results: Our end-to-end solution allow parallelized, fully automated processing of formalin-fixed or paraffin-embedded tissues of 1cm³ size. With a tissue-to-image time of 6 days, the whole intact tissue block can be non-destructively imaged with our newly developed 3D HnE (Hematoxylin-analogue & Eosin stain) and 4-plex immunohistochemistry (IHC). Deep and homogeneous penetration of staining was achieved such that all stained markers can be quantified as ground truth. The stained and cleared tissue can be recycled for subsequent FFPE 2D histology over multiple cycles for higher-plex imaging, and is also applicable to simultaneous survey of mRNA with multiplexed fluorescent in situ hybridization (FISH), post-translational modifications such as histone modifications via IHC, and glycosylation profiling with lectins. Image analysis readily allows high-dimensional clustering of cells based on their multi-modal biomolecular expression profiles, morphology, spatial locations, and neighborhoods. The method is applicable to a wide variety of human and murine tissues. Conclusions: Our 3D digital pathology platform enables maximal information extracted for precision diagnostics and advanced biomedical research.