The Wuyi-Yunkai Orogeny (WYO) in South China occurred during the assembly of Gondwana, and has abundant granites and migmatites which have been mostly interpreted as products of dehydration anatexis. However, the early Paleozoic migmatites in the Cathaysia Block, investigated in this study, instead document water-fluxed anatexis during the orogeny. The quartzo-feldspathic migmatites are moderately peraluminous, and have ca. 700 Ma and ca. 1800 Ma inherited zircon sub-populations, indicating that they were derived from Middle Neoproterozoic paragneisses. Titanite is common, while other anhydrous peritectic minerals such as garnet and pyroxene are absent in the migmatites and their leucosomes. Both mineral assemblages and microstructures indicate that the rocks were melted through reactions that include quartz + plagioclase + biotite + H2O = titanite + opaque + melt, K-feldspar + plagioclase + quartz + H2O = melt, and K-feldspar + biotite + quartz + H2O = melt. U-Pb ages of the newly-formed zircon and titanite display at least four age populations, recording episodic melting mainly at ca. 466, 437, 425 and 412 Ma, with evidence of local anatexis extending back to at least 480 Ma. Multiple stages of anatexis with short time intervals may have resulted from water-present melting due to episodic fluid influx. Zircon εHf(t) values are negative (-5 to -15) in the 700 Ma and 1800 Ma inherited zircons to nearly zero (0 to -5) in 470–400 Ma newly-formed zircons, and may have resulted from dissolution of the Lu-rich apatite during water-fluxed anatexis. The newly-formed zircons also have high δ18O values (9–12 ‰). These lines of evidence suggest that fluid flux-influenced melting was induced by metamorphic fluids that were released from polyphase metamorphism during crustal thickening and extension in the WYO, and channelized through regional shear zones. This highlights the extent and significance of water-fluxed anatexis and its role in the differentiation of the continental crust during orogeny.