Validating MRI data against histological ground truth is essential in the process of devising disease-specific imaging biomarkers that are sensitive to early microstructural changes in neurodegeneration. Current MRI–histology registration techniques are too labour- or resource-intensive to be used in large-scale studies. We introduce an automated pipeline for registering sparsely sampled, small (25x30mm) 2D stained histological images with 3D post-mortem MRI of the whole human brain. Our tests indicate sub-voxel (<0.5 mm) precision using simulated data, and <1 mm precision with real data. Implemented in a new, flexible image registration framework (TIRL), the pipeline is adaptable to various research needs.