This paper discusses the Cenozoic interaction of regional tectonics and climate changes. These processes were responsible for mass flux from mountain belts to depositional basins in the eastern Alpine retro-foreland basin (Venetian–Friulian Basin). Our discussion is based on the depositional architecture and basin-scale depositional rate curves obtained from the decompacted thicknesses of stratigraphic units. We compare these data with the timing of tectonic deformation in the surrounding mountain ranges and the chronology of both long-term trends and short-term high-magnitude (‘aberrant’) episodes of climate change. Our results confirm that climate forcing (and especially aberrant episodes) impacted the depositional evolution of the basin, but that tectonics was the main factor driving sediment flux in the basin up to the Late Miocene. The depositional rate remained below 0.1 mm year−1 on average from the Eocene to the Miocene, peaking at around 0.36 mm year−1, during periods of maximum tectonic activity in the eastern Southern Alps. This dynamic strongly changed during the Pliocene–Pleistocene, when the basin-scale depositional rate increased to an average of 0.26 mm year−1 (Pliocene) and 0.73 mm year−1 (Pleistocene). This result fits nicely with the long-term global cooling trend recorded during this time interval. Nevertheless, we note that the timing of the observed increase may be connected with the presumed onset of major glaciations in the southern flank of the Alps (0.7–0.9 Ma), the acceleration of the global cooling trend (since 3–4 Ma) and climate variability (in terms of magnitude and frequency). All these factors suggest that combined high-frequency and high-magnitude cooling–warming cycles are particularly powerful in promoting erosion in mid-latitude mountain belts and therefore in increasing the sediment flux in foreland basins.