The Southeast Trans-Baikal region in Russia hosts large and super large Mesozoic polymetallic mineral deposits including chalcophile and lithophile elements, rare metals, rare earth elements, and uranium. Here, we analyse the salient features of this metallogenic belt in terms of their distribution, mineral speciation, and relation to regional structures. The deep mantle architecture beneath this region is analyzed from published geophysical data including seismic tomography. The results show that the highly productive ores are largely located above the axial line of an undulating Moho that projects from the apex region of a subducted slab stagnant in the mantle transition zone. We propose that thermal and fluid flux from the asthenospheric mantle, metasomatism of the overlying shallow mantle, and mantle–crust interaction intensified the magmatism associated with metallogeny. Our study provides an example for deep-seated geodynamics influencing the formation and distribution of giant ore belts.