Quantitative analysis of crustal thickness evolution across past geological periods poses significant challenges but provides invaluable insights into the planet’s geological history. It may help uncover new areas with potential critical mineral deposits and reveal the impacts of crustal thickness and elevation changes on the development of the atmosphere, hydrosphere, and biosphere. However, a significant knowledge gap in reconstructing regional paleo-crustal thickness distribution is that most estimation proxies are limited to arc-related magmas. By mining extensive geochemical data from present-day subduction zones, collision orogenic belts, and non-subduction-related intraplate igneous rock samples worldwide, along with their corresponding Moho depths during magmatism, we have developed a machine learning-based mohometry linking geochemical data to Moho depth, which is universally applicable in reconstructing ancient orogenic systems’ paleo-crustal evolution and tracking complex tectonic histories in both spatial and temporal dimensions. Our novel mohometry model demonstrates robust performance, achieving an R² of 0.937 and RMSE of 4.3 km. Feature importance filtering highlights key geochemical proxies, allowing for accurate paleo-crustal thickness estimation even when many elements are missing. The mohometry validity is demonstrated through applications to southern Tibet, which has well-constrained paleo-crustal thicknesses, and the South China Block, which is noted for its complex tectonic evolution and extensive 800-km-wide Cretaceous extensional system. Additionally, the evolution of reconstructed paleo-crustal thickness, particularly in areas with anomalously thick crust, strongly correlates with porphyry ore deposits. These findings offer valuable insights for prospecting for new porphyry ore deposits, particularly in ancient orogens where significant surface erosion has occurred.