The processes responsible for the compositional evolution of metamorphic terranes that underwent disequilibrium melting reactions control the petrology, the geochemistry and the isotopic composition of the resulting anatectic magmas. The high-grade metamorphic Tarra Padedda Complex (northern Sardinia, Italy) provides a suitable opportunity to study the isotopic (Sr–Nd) and geochemical evolution of both the anatectic magmatic products and their source. The metamorphic complex consists of migmatites (diatexites, metatexites and hornblende-bearing migmatites) and sillimanite-bearing metasediments, which were intruded by syntectonic peraluminous granitoids, aplites and pegmatites. The diatexites consist of stromatic migmatites and nebulites. Neosomes in stromatic migmatites show either granitic or trondhjemitic leucosomes, and hornblende-bearing or hornblende-free melanosomes. Petrographic characteristics of the melanosomes and hornblende-bearing migmatites suggest two distinct biotite-dehydration melting reactions: (a) biotite + sillimanite + plagioclase + quartz → garnet ±K-feldspar + melt; and (b) biotite + plagioclase (An~40) + quartz → hornblende + plagioclase (An > 60) + titanite + melt. In contrast, textural features in metatexites favour dehydration melting of muscovite: muscovite + quartz + plagioclase → sillimanite + K-feldspar + melt. A progressive variation of chemical composition coupled with a decrease of Sr and Nd crustal isotopic signatures is observed both within the metamorphic rocks and the granitoids. Field relationships, petrological, geochemical and isotope evidence of the Tarra Padedda Complex are consistent with a multi-stage anatexis of a heterogeneous metasedimentary source within the same Hercynian orogenic cycle. The variation of Sr and Nd isotope compositions within both the granitoids and the migmatites is interpreted in terms of anatexis of the various metasedimentary components, via different melting reactions involving micas plus variable amounts of accessory phases (apatite, monazite, zircon and/or xenotime).