The study of the Earth’s crust and particularly the estimation of Moho discontinuity depths, based both on seismic and gravity data, is generally identified as a topic of great geophysical interest. The present work further expands on the topic of Moho depth estimation from initial gravity data information with high accuracy, for a geophysically interesting region that covers the majority of the Greek mainland, using both GOCE processed data and information obtained from Global Geopotential Models (GGM). The primary method for Moho depth estimation was the Parker-Oldenburg one, which was applied by using as input data GOCE and GGM based complete Bouguer gravity anomalies in the aforementioned region. Moho depth estimation experiments based on the inverse problem of isostasy of Vening Meinesz–Moritz (VMM) were also applied in the aforementioned region. The estimated Moho models for the Greek mainland were validated against seismic data in the area of interest along with information available from regional crustal models. From the results acquired, the largest values of Moho depths in the selected area were identified beneath the Hellenides (found in most cases to be over 40 km), while the smallest ones were found in the Southern Aegean as well as in the sea area southwestern of the Peloponnese.