Understanding lithosphere structure across craton–margin transitions remains a major challenge, particularly in data-scarce intraplate regions. This study integrates terrestrial gravimetry, satellite-derived gravity fields, topography, and seismological constraints to investigate crust–mantle interactions across the Congo Craton (CC), Pan-African Belt (PAB), and Cameroon Volcanic Line (CVL). Regional gravity anomalies were inverted using a Parker–Oldenburg approach to derive Moho depth variations, with sensitivity tests on density contrast and reference depth to assess model robustness. Isostatic compensation was evaluated by comparing gravity-derived Moho geometry with topography-based models. The results reveal pronounced lateral variations in crustal thickness and isostatic state across major tectonic domains. Overcompensated crust characterizes the coastal plain and parts of the Pan-African domain, whereas undercompensated crust is observed beneath the Cameroon Volcanic Line and the southern margin of the Congo Craton. These patterns indicate that local isostatic equilibrium alone cannot explain the observed topography, highlighting the roles of crustal stretching, sedimentary loading, inherited tectonic structures, and possible mantle-driven processes. Abrupt changes in compensation correlate with seismicity (M > 3.5), highlighting lithospheric disequilibrium as a driver of regional tectonic hazards. The northern CC margin and Mount Cameroon emerge as active extension zones with implications for future earthquakes.By integrating gravity, topography, and seismic constraints, this work provides new insights into the architecture and evolution of the continental lithosphere from craton to margin and supports multiphysics approaches linking surface processes to deeper geodynamic mechanisms.