Whole-brain mesoscale mapping has been hindered by large brain sizes and the relatively low throughput of available microscopy methods. Here, we present an approach that combines primate-optimized tissue sectioning and clearing with ultrahigh-speed fluorescence microscopy implementing improved volumetric imaging with synchronized on-the-fly-scan and readout (VISoR), and is capable of completing whole-brain imaging of a rhesus monkey at 1 Å~ 2.5 μm3 voxel resolution within 100h. We also developed a highly efficient method for long-range tracing of sparse axonal fibers in datasets numbering hundreds of terabytes. This pipeline enables effective connectome-scale mapping of large primate brains.