The rapid growth of the Amazon deep-sea fan following the Andean uplift led to its gravitational collapse, forming upstream extensional domains and downstream thrust belts. The Amazon fan consists of two compartments with significant structural differences: one thick and extended compartment in the Northwest (NW), and a thinner and more restricted compartment in the Southeast (SE). This study examines whether these different structural geometries can be attributed to spatial and temporal variations in overpressure generation mechanisms, using petroleum systems analysis techniques. We first show that over the last 8Ma, overpressure gradually increased in the fan and deformation and overpressure migrated basinward along the detachment surface for both compartments. However, overpressure mechanisms differed significantly between the two compartments. In the SE, disequilibrium compaction driven by high rates of sedimentary input from the Amazon River, appears to be the primary mechanism of overpressure, while in the NW, thermogenic gas generation and smectite-to-illite transformation are the main overpressure generation mechanisms. Finally, we discuss how, in addition to variations in sedimentation rates over time, the differing timing of thermogenic gas generation and/or the role of these hydrocarbons as an overpressure mechanism could be linked to the thermal history of the Foz do Amazonas basin, and thus to its structural heritage, in particular the nature of the basin substratum on a segmented margin.