We present a minero-petrographic, geochemical and geochronological study of siderite orebodies from different localities of the Southern Alps (northern Italy). Siderite occurs as veins cutting the Variscan basement and the overlying Lower Permian volcano-sedimentary cover (Collio Fm.), and as both veins and conformable stratabound orebodies in the Upper Permian (Verrucano Lombardo and Bellerophon Fms.) and Lower Triassic (Servino and Werfen Fms.) sedimentary sequences of the Lombardian and the Venetian Alps. All types of deposits show similar major- and rare-earth (REE)-element patterns, suggesting a common iron-mineralizing event. The compositions of coexisting siderite, Fe-rich dolomite and calcite suggest formation from hydrothermal fluids at relatively high temperature conditions (≥ 250 °C). Geochemical modelling, supported by REE analyses and by literature and new δ13C and δ18O isotopic data, suggests that fluids responsible for the formation of siderite in the Variscan basement and in the overlying Lower Permian cover were derived from dominant fresh water, which leached Fe and C from volcanic rocks (mainly rhyolites/rhyodacites) and organic carbon-bearing continental sediments. On the basis of U-Th-Pb microchemical dating of uraninite associated with siderite in the Val Vedello and Novazza deposits (Lombardian Alps), the onset of hydrothermalism is constrained to 275 ± 13 Ma (Early–Mid Permian), i.e., it was virtually contemporaneous to the plutonism and the volcanic-sedimentary cycle reported in the same area (Orobic Basin). The youngest iron-mineralizing event is represented by siderite veins and conformable orebodies hosted in Lower Triassic shallow-marine carbonatic successions. In this case, the siderite-forming fluids contained a seawater component, interacted with the underlying Permian successions and eventually replaced the marine carbonates at temperatures of ≥ 250 °C. The absence of siderite in younger rocks suggests an Early Triassic upper limit for the iron pulse in the Southern Alps, which would thus predate the Middle Triassic magmatism. Based on the overlap between hydrothermalism, extensional tectonics and, in part, magmatism, the genesis of siderite in the Southern Alps may be related to plutonic activity and/or magmatic underplating occurring since the Permian in a geodynamic scenario preluding the opening of the Neo-Tethys.