Chemical probes are key components of the bioimaging toolbox, as they label biomolecules in cells and tissues. The new challenge in bioimaging is to design chemical probes for three-dimensional (3D) tissue imaging. In this work, we discovered that light scattering of metal nanoparticles can provide 3D imaging contrast in intact and transparent tissues. The nanoparticles can act as a template for the chemical growth of a metal layer to further enhance the scattering signal. The use of chemically grown nanoparticles in whole tissues can amplify the scattering to produce a 1.4 million-fold greater photon yield than obtained using common fluorophores. These probes are non-photobleaching and can be used alongside fluorophores without interference. We demonstrated three distinct biomedical applications: (a) molecular imaging of blood vessels, (b) tracking of nanodrug carriers in tumors, and (c) mapping of lesions and immune cells in a multiple sclerosis mouse model. Our strategy establishes a distinct yet complementary set of imaging probes for understanding disease mechanisms in three dimensions.