The Pikwitonei Granulite Domain located at the northwestern margin of the Superior Province is one of the largest Neoarchean high-grade terranes in the world, with well-preserved granulite metamorphic assemblages preserved in a variety of lithologies, including enderbite, opdalite, charnockite, and mafic granulite. U–Pb geochronology has been attempted to unravel the protolith ages and metamorphic history of numerous lithologies at three main localities; Natawahunan Lake, Sipiwesk Lake, and Cauchon Lake. The U–Pb age results indicate that some of the layered enderbite gneisses are Mesoarchean (3.4–3.0 Ga) and the more massive enderbites are Neoarchean. The high-grade metamorphic history of the Pikwitonei Granulite Domain is complex and multistage with at least four episodes of metamorphic zircon growth identified: (1) 2716.1 ± 3.8 Ma, (2) 2694.6 ± 0.6 Ma, (3) 2679.6 ± 0.9 Ma, and (4) 2642.5 ± 0.9 Ma. Metamorphic zircon growth during episodes 2 and 3 are interpreted to be regional in extent, corresponding to M1 amphibolite- and M2 granulite-facies events, respectively, consistent with previous field observations. The youngest metamorphic episode at 2642.5 Ma is only recognized at southern Cauchon Lake, where it coincides with granite melt production and possible development of a major northeast-trending deformation zone. The timing and multistage metamorphic history recorded in the Pikwitonei Granulite Domain is similar to most Superior Province high-grade terranes and marks a fundamental break in Archean crustal evolution worldwide at the termination of prolific global Neoarchean greenstone belt formation.