The evolution of the Palaeozoic Southern Cantabrian Basin is quantified by a multidisciplinary approach of structural balancing, reverse-basin and forward stratigraphic modelling. These methods were applied to the N-S trending, 54 km long Bernesga Transect in the Cantabrian Mountains. Total tectonic shortening of the Southern Cantabrian Basin amounted to a minimum of 54%. These data were derived from two-dimensional structural balancing of the deformed basin infill. Two-dimensional reverse-basin modelling was used for analysing the evolution of the basin architecture, considering lithofacies, incremental compaction, eustatic sea-level changes and flexural loading of the crust. The model comprises the entire basin infill between the top of the Neoproterozoic basement and the time of maximal burial (Cenozoic). Six major subsidence trends, with time spans between 9 and 65 Myr, subdivide the long-term evolution of accommodation space in time. These trends reflect different lithospheric configurations prior to, during and after the Variscan Orogeny, having been primarily triggered by major changes in thermo-tectonic and flexure-induced subsidence, as well as by regional and extraregional tectonics. Basin modelling permits the identification of two encroachment subcycles during the Silurian and Devonian, as well as the approach of the Variscan orogenic front in the Early Carboniferous. The latter is reflected by migrating, strongly subsiding depocentres (orogenic foredeep), controlled by increased flexural-induced and thermo-tectonic subsidence. Two-dimensional stratigraphic forward modelling was used to simulate the evolution of the Southern Cantabrian Basin, and to quantify internal and external parameters governing deposition (e.g. sediment transport, sedimentation rates, in-situ carbonate production, erosion and compaction). The model includes data from the Neoproterozoic to the Lower Carboniferous with a focus on the Devonian. Carbonate factories in the Devonian were controlled by fluctuating siliciclastic input and differential thermo-tectonic subsidence, and subordinately influenced by eustatic sea-level changes. Decompacted carbonate production rates reach up to 780 m Myr −1 . The changes in carbonate production rates mirror the drift of Iberia from cooler to subtropical/tropical conditions during Devonian times.