The Brazilian Equatorial Margin is strongly influenced by sediment supply from the Amazon River, where the Plio-Pleistocene succession lacks geochronological data making the stratigraphic architecture of this continental margin and its driving mechanisms poorly understood. Here we study a shelf-edge area of the Brazilian Equatorial Margin when siliciclastic deposition started around 3.7 to 4 Ma immediately after the well-known Amapá carbonate platform. We perform a coupled approach of sequence stratigraphic analysis of a 3D seismic block, and cyclostratigraphic analysis of gamma-ray (GR) log data from three exploration wells. We identify nine main seismic sequences since the onset of siliciclastic deposition. Cyclostratigraphic analyses indicate that each seismic sequence corresponds to a long 405 kyr eccentricity cycle. Additionally, we show that the nine 405 kyr eccentricity related seismic sequences are grouped into three depositional mega-sequences (MS-I through MS-III), which mark major changes in stratal architecture along the Brazilian Equatorial shelf edge. Orbitally calibrated mega-sequence boundaries yield ages of 3.7, 2.4 and 0.8 Ma for the bases of MS-I, MS-II and MS-III respectively. Correlation of these mega-sequence boundaries with the global sea-level change suggests that long-term increase in the amplitude of sea-level fluctuations is likely the primary driver of these major sedimentary changes. We suggest that basal mega-sequence boundaries of MS-II and MS-III at 2.4 and 0.8 Ma may reflect important steps in the Earth's Quaternary climate and sea level, specifically overall cooling that led to the intensification of Northern Hemisphere Glaciations (iNHG) and the Mid-Pleistocene Transition (MPT). Finally, a further significant change in shelf edge architecture at around 0.4 Ma corresponds to a change from mostly prograding patterns since 0.8 Ma to mostly aggrading ones during the last 405 kyr. This shift in the depositional system is likely related to the prominent high amplitude sea-level rise characterizing the long-lasting Marine Isotopic Stage 11.