Abstract. The seismogenesis of rocks is mainly affected by their mineral composition and in situ conditions (temperature and state of stress). Diverse laboratory experiments have explored the frictional behaviour of the rocks and rock-forming minerals most common in the crust and uppermost mantle. However, it is debated how to “upscale” these results to the lithosphere. In particular, most earthquakes in the crust nucleate down to the crustal seismogenic depth (CSD), which is a proxy for the maximum depth of crustal earthquake ruptures in seismic hazard assessments. In this study we propose a workflow to upscale and validate those laboratory experiments to natural geological conditions relevant for crustal and upper-mantle rocks. We used the southern Caribbean and northwestern South America as a case study to explore the three-dimensional spatial variation of the CSD (mapped as D90, the 90 % percentile of hypocentral depths) and the temperatures at which crustal earthquakes likely occur. A 3D steady-state thermal field was computed for the region with a finite-element scheme using the software GOLEM, considering the uppermost 75 km of a previously published 3D data-integrative lithospheric configuration, lithology-constrained thermal parameters, and appropriate upper and lower boundary conditions. The model was validated using additional, independent measurements of downhole temperatures and heat flow. We found that the majority of crustal earthquakes nucleate at temperatures less than 350 ∘C, in agreement with frictional experiments of typical crustal rocks. A few outliers with larger hypocentral temperatures evidence nucleation conditions consistent with the seismogenic window of olivine-rich rocks, and can be due to either uncertainties in the Moho depths and/or in the earthquake hypocentres or the presence of ultramafic rocks within different crustal blocks and allochthonous terranes accreted to this complex margin. Moreover, the spatial distribution of crustal seismicity in the region correlates with the geothermal gradient, with no crustal earthquakes occurring in domains with low thermal gradient. Finally, we find that the largest earthquake recorded in the region (Mw=7.1, Murindó sequence, in 1992) nucleated close to the CSD, highlighting the importance of considering this lower-stability transition for seismogenesis when characterizing the depth of seismogenic sources in hazard assessments. The approach presented in this study goes beyond a statistical approach in that the local heterogeneity of physical properties is considered in our simulations and additionally validated by the observed depth distribution of earthquakes. The coherence of the calculated hypocentral temperatures with those expected from laboratory measurements provides additional support to our modelling workflow. This approach can be applied to other tectonic settings worldwide, and it could be further refined as new, high-quality hypocentral locations and heat flow and temperature observations become available.