ABSTRACT Process-based Forest Models (PBFMs) offer the possibility to capture important spatial and temporal patterns of carbon fluxes and stocks in forests. Yet, their predictive capacity should be demonstrated not only at the stand-level but also in the context of broad spatial and temporal heterogeneity. We apply a stand scale PBFM (3D-CMCC-FEM) in a spatially explicit manner at 1 km resolution in southern Italy. We developed a methodology to initialize the model that includes information derived from the integration of Remote Sensing (RS) and the National Forest Inventory (NFI) data and regional forest maps to characterize structural features of the main forest species. Gross primary production (GPP) is simulated over 2005–2019 period and the model predictive capability of the model in simulating GPP is evaluated both aggregated as at species-level through multiple independent data sources based on different nature RS-based products. We show that the model is able to reproduce most of the spatial (~2800 km2) and temporal (32 years in total) patterns of the observed GPP at both seasonal, annual and interannual time scales, even at the species-level. These promising results open the possibility of confindently applying the 3D-CMCC-FEM to investigate the forests’ behaviour under climate and environmental variability over large areas across highly variable ecological and bio-geographical heterogeneity of the Mediterranean region.