We applied magnetostratigraphy and mammal biostratigraphy to date climate-sensitive pollen cycles and lithostratigraphic units of the Pliocene–Pleistocene Leffe sedimentary succession from the Southern Alps, Italy. The Leffe section was correlated to additional sections (Casnigo, Fornaci di Ranica, and Pianengo) to construct a stratigraphic network along a common fluviatile system (the Serio River) sourced in the Southern Alps and flowing southward into the Po River Basin. We obtained a coherent scenario of climate variability for the last ∼ 2 Myr. At Leffe, lacustrine deposition commenced during the Olduvai Normal Subchron (1.94–1.78 Ma) and lasted up to a chronologic level compatible with Marine Isotope Stage (MIS) 22 (0.87 Ma). Pollen analysis revealed that climate varied cyclically from warm-temperate to cool during this time interval, but never as cold as during glacial intervals. At around MIS 22, climate cooled globally. Gravels, attributed to high-energy braided river systems fed locally by alluvial fans, prograded from the Serio River catchment area over the Leffe Basin and toward the Po Plain in response to a generalized event of vegetation withdrawal and enhanced physical erosion. At this time, Alpine valley glaciers reached their first maximum southward expansion with glacier fronts located at only ∼ 5 km upstream from Leffe.