Neoproterozoic igneous rocks of the Avalonian Mira terrane, Cape Breton Island, and Caledonia terrane, southern New Brunswick, have experienced regional 18O-depletion. The majority of these rocks have δ18OWR values between −1 and +6‰, markedly different from igneous rocks of the inboard Ganderian terranes, which have normal-high δ18OWR values of +7 to +12‰. The 18O-depletion of these Avalonian terranes resulted from pervasive hydrothermal alteration. All of the igneous rocks contain classic propylitic alteration assemblages of turbid feldspar, chlorite, epidote, sericite, and calcite and host multiple generations of veins containing the same phases. The δ18O values of the rock-forming minerals show strong disequilibrium with Δqtz-fs ranging from +2.5 to +11.0‰ and Δkfs-plg from −0.5 to +1.0‰. Such values are indicative of post-magmatic hydrothermal alteration. The hydrothermal alteration occurred at ca. 560–550 Ma during initial transcurrent rifting of Avalonia at the Gondwanan margin. The development of rift-wrench basins with associated bimodal volcanism allowed large volumes of hydrothermal fluids to penetrate and circulate within Mira and Caledonia terrane crust before its submergence in the early Cambrian (ca. 540–530 Ma). The hydrothermal fluids were predominantly meteoric, although the presence of a significant seawater component cannot be ruled out. The almost ubiquitous 18O-depletion exhibited by the Neoproterozoic rocks in these Avalonian terranes is absent in the associated Ganderian terranes, suggesting that Avalonia remained separate from Ganderia until at least the Cambrian-Ordovician. This 18O-depletion provides an additional geochemical tool for identification of Avalonian crust in other areas of the Appalachians and Europe.