The Late Cretaceous is a critical period in the evolution of the South Atlantic. Significant changes in the tectonic configuration of continental landmasses and marine basins during this time lead to major shifts in the sedimentary and oceanographic regimes. Using a combination of 2D and 3D seismic data with well data from the Uruguayan Margin, this work provides a new, highly detailed description of the Late Cretaceous sedimentary evolution of the margin and its regional and global palaeoceanographic implications.The Polonio Drift System (PDS), occupies the middle to lower-slope of the Uruguayan Margin. The PDS is characterised by four channel-drifts, which propagate obliquely (120–170°) from the palaeoslope and exhibit over 800m of local relief relative to the surrounding seafloor. Seismic interpretation identified four seismic units (SU.1–SU.4), separated by five major discontinuities (R.1–R.5). These record the onset (Albian–upper Turonian, 113–89.8Ma), growth (Coniacian–upper Maastrichtian, 89.8–66Ma), and burial (Paleocene, 66–56Ma) phases for the PDS. During the onset stage, down-slope processes dominate but, three major shifts in the sedimentary stacking pattern occur. These coincide with palaeoceanographic changes in the South Atlantic during the Cenomanian–Turonian (100.5–89.9Ma), Campanian-Maastrichtian (83.6–66Ma) and Paleocene (66–56Ma), following the opening of the Falkland/Malvinas-Agulhas Seaway (FAS), the subsidence of the Walvis-Ridge and the opening of the Vema channel. Bottom current influence first occurs during the growth stage (Coniacian–Campanian) when mounded deposits shift from aggradational and slightly progradational towards the N (SU.2), to clear lateral migration towards the S (SU.3). This sedimentary pattern indicates a regional palaeoceanographic shift in bottom current flow from northerly, to a subsequent southerly direction. Bottom currents do not appear to have actively eroded sediment, although they apparently had the potential to pirate and entrain fine-grained material from turbidity plumes, which build on underlying bathymetric features such as basement horsts and channel-levees. These produce large mounded morphologies adjacent to channels. Drift growth ceases following the termination of shelf progradation (R.4), enabling sluggish bottom currents contributed to a homogeneous sedimentary drape. Bottom currents intensify in the beginning of the Paleocene, forming contourite depositional systems with well-developed contourite terrace along the middle slope. Further research can elucidate the nature and mechanics of turbidite–contourites interactions along continental margins. This work offers new insights for the implications and consequences of the interaction of turbidites and contourites, which can improve the characterisation of deep-water deposits and understanding palaeoceanographic interpretations.