The Precordillera mafic–ultramafic belt (PMUB), located in central-western Argentina, comprises mafic and ultramafic bodies interlayered and/or in tectonic contact with marine siliciclastic units. Whole-rock, mineral geochemistry and Nd–Sr isotope analyses performed in magmatic rocks suggest a relatively different spatial and temporal evolution along the belt. The southern PMUB (south of 32° S) evolved as an intra-continental rifted margin with an enriched mid-ocean-ridge basalt (E-MORB) tholeiitic to alkaline magmatism, to a proto-ocean basin (the Cuyano proto-ocean) with tholeiitic normal-MORB geochemical signature. Based on neodymium model ages (TDM), the magmatic activity started during the late Neoproterozoic Era and continued into the early Palaeozoic Era. Instead, the northern PMUB (28–32° S) evolved as an intra-continental rifted margin with dominant tholeiitic E-MORB to continental flood basalt (CFB) magmatism during the early Palaeozoic Era. ϵNd values (+3.4 to +8.4), rare earth element trends and high-field-strength element systematics, together with an estimated potential mantle temperature of c. 50–100°C above ambient mantle, suggest the PMUB magmatism derived from an enriched mantle source related to the effect of a rising plume linked to the Iapetus Ocean opening. In particular, TDM estimations of 600–550 Ma agree with reported magmatism in central to southern Appalachians. The magmatism in the PMUB, and those registered in the Neoproterozoic Catoctin Formation and in the Southern Oklahoma Aulacogen in the conjugated Laurentian margin, seem to be contemporaneous, sharing a similar plume-enriched mantle source. In this context, the E-MORB signature identified along the PMUB can be described as a plume-distal ridge tectonic setting over an extended margin.