Silurian to Devonian granites within the Gander Zone of the Appalachian Central Mobile Belt in northeastern Newfoundland formed adjacent to the former Gondwanan continental margin following terminal closure of the Iapetus Ocean. Comparison of geochemical and isotopic characteristics of the granites with their host migmatites and metasediments, amphibolite, and orthogneiss constrain their potential source. Nd and Sr isotopic compositions indicate that no single source or binary mixing product could have produced the granites. Instead, we show that they result from multicomponent mixing involving a contribution from unexposed crystalline basement, mantle or underplate, and variable contamination by supracrustal host rocks. The timing and composition of granite magmatism do not exhibit collisional orogenic, subduction-related, or continental rifting characteristics. Hence, we relate magmatism to lithospheric melting following delamination of an orogenic keel. This process provides the influx of mantle-derived magma into fertile crust and hence promotes lower crustal melting and primary magma mixing.