The crustal seismogenic thickness (CST) has direct implications on the magnitude and occurrence of crustal earthquakes, and therefore, on the seismic hazard of high-populated regions. Amongst other factors, the seismogenesis of rocks is affected by in-situ conditions (temperature and state of stress) and by their heterogeneous composition. Diverse laboratory experiments have explored the frictional behavior of the most common materials forming the crust and upper most mantle, which are limited to the scale of the investigated sample. However, a workflow to up-scale and validate these experiments to natural geological conditions of crustal and upper mantle rocks is lacking. We used NW South America as a case-study to explore the spatial variation of the CST and the potential temperatures at which crustal earthquakes occur, computing the 3D steady-state thermal field taking into account lithology-constrained thermal parameters. Modelled hypocentral temperatures show a general agreement with the seismogenic windows of rocks and mineral assemblies expected in the continental crust. A few outliers in the hypocentral temperatures showcase nucleation conditions consistent with the seismogenic window of olivine-rich rocks, and are intepreted in terms of uncertainties in the Moho depths and/or in the earthquake hypocenters, or due to the presence of ultramafic rocks within the allochthonous crustal terranes accreted to this complex margin. Our results suggest that the two largest earthquakes recorded in the region (Murindo sequence, in 1992) nucleated at the lower boundary of the seismogenic crust, highlighting the importance of considering this transition into account when characterizing seismogenic sources for hazard assessments.