Fluid–rock interaction within the altered oceanic crust and across the slab–mantle boundary during subduction facilitates element transfer, but the dynamics of fluid transport and fluid–rock exchange during upward fluid migration are still unclear. A study of metamorphic fluid–rock interaction within a section of subducted oceanic crust was carried out on eclogites and metasediments of the ultra-high-pressure Lago di Cignana Unit (NW Italian Alps). The P–T modeling of a quartzschist shows that garnet grew during the prograde and sporadically during the retrograde path and that phengite mainly records the peak to retrograde conditions. Microscale geochemical analysis of garnets has revealed a systematic evolution of oxygen isotopic composition with garnet major element zonation, with extreme within-sample core–rim variations in δ18O between 18 and 4‰ providing evidence for external fluid influx. Garnet in eclogites and calcschists, as well as garnet cores in quartz-rich lithologies, shows normal compositional zoning, as expected for prograde garnet growth, and a relatively constant oxygen isotopic composition. The outer garnet growth zones within a few metasediments show reverse or discontinuous zoning and progressively lower δ18O. Despite major element zoning, the isotopic composition of mica is homogeneous across chemical zoning in one eclogite and one quartzschist, but shows 6‰ variability in another quartzschist. In the underlying Zermatt–Saas serpentinites, antigorite from nine serpentinite samples shows some variation in δ18O, with average δ18O values for individual samples ranging from 1 to 6‰. These results provide evidence for two main stages of external fluid infiltration: (i) fluids from the dehydration of mafic lithologies entered the sequence at peak conditions around 3 GPa, as indicated by the oxygen composition of intermediate zones of mica and garnet, and (ii) low δ18O fluids from serpentinites infiltrated parts of the sedimentary package during exhumation prior to 1.5 GPa, as recorded by the 4‰ garnet outer rims. Samples recording external fluid infiltration are concentrated in the lower part of the sequence, indicating channelized fluid flow, suggesting focused fluid infiltration due to permeability contrasts between metasedimentary and eclogitic lithologies. Channelized fluid flow in the ultra-high-pressure metasediments of Lago di Cignana has not resulted in systematic decarbonation of the metasediments.