We report a study of whole-rock O–H–Sr–Nd isotopes of Ordovician igneous and metamorphic rocks exposed at different crustal palaeodepths along c. 750 km in the Sierras Pampeanas, NW Argentina. The isotope compositions preserved in the intermediate rocks (mostly tonalite) (average δ18O = +8.7 ± 0.5‰, δD = −73 ± 14‰, 87Sr/86Srt = 0.7088 ± 0.0001 and εNdt = −4.5 ± 0.6) show no major difference from those of most of the mafic rocks (average δ18O = +8 ± 0.8‰, δD = −84 ± 18‰, 87Sr/86Srt = 0.7082 ± 0.0016 and εNdt = −4 ± 1.1), suggesting that most of their magmas acquired their crustal characteristics in the mantle. The estimate of assimilation of crustal material (δ18O = +12.2 ± 1.7‰, δD = −89 ± 21‰, 87Sr/86Srt = 0.7146 ± 0.0034 and εNdt = −6.9 ± 0.7) by the tonalite is in most samples within the range 10–20%. Felsic magmas that reached upper crustal levels had isotope values (δ18O = +9.9 ± 1.5‰, δD= −76 ± 5‰, 87Sr/86Srt = 0.7067 ± 0.0010, εNdt = −3.5 ± 1.4) suggesting that they were not derived by fractionation of the contaminated intermediate magmas, but evolved from different magma batches. Some rocks of the arc, both igneous (mostly gabbro and tonalite) and metamorphic, underwent restricted interaction with meteoric fluids. Reported values of δ18O of magmatic zircons from the Famatinian arc rocks (+6 to +9‰) are comparable to our δ18O whole-rock data, indicating that pervasive oxygen isotope exchange in the lower crust was not a major process after zircon crystallization.