Recently, major progress has been made in the simulation of the ocean dynamics of the Mediterranean using atmospheric and oceanic models with high spatial resolution. High resolution is essential to accurately capture the synoptic variability required to initiate intermediate-and deep-water formation, the engine of the Mediterranean thermohaline circulation (MTC). In paleoclimate studies, one major problem with the simulation of regional climate changes is that boundary conditions are not available from observations or data reconstruction to drive high-resolution regional models. One consistent way to advance paleoclimate modelling is to use a comprehensive global-to-regional approach. However, this approach needs long-term integration to reach equilibrium (hundreds of years), implying enormous computational resources. To tackle this issue, a sequential architecture of a global-regional modelling platform has been developed for the first time and is described in detail in this paper. First of all, the platform is validated for the historical period. It is then used to investigate the climate and in particular, the oceanic circulation, during the Early Holocene. This period was characterised by a large reorganisation of the MTC that strongly affected oxygen supply to the intermediate and deep waters, which ultimately led to an anoxic crisis (called sapro-pel). Beyond the case study shown here, this platform may be applied to a large number of paleoclimate contexts from the Quaternary to the Pliocene, as long as regional tectonics remain mostly unchanged. For example, the climate responses of the Mediterranean basin during the last interglacial period (LIG), the Last Glacial Maximum (LGM) and the Late Pliocene all present interesting scientific challenges which may be addressed using this numerical platform.