The ultramafic-mafic Talnakh intrusion in the Norilsk province (Russia) hosts one of the world’s major platinum group element (PGE)-Cu-Ni sulfide deposits. This study employed a multitechnique approach, including in situ Hf-O isotope analyses of zircon combined with whole-rock Nd isotope data, in order to gain new insights into genesis of the Talnakh economic intrusion. Zircons from gabbrodiorite, gabbroic rocks of the layered series, and ultramafic rocks have similar mantle-like mean δ18O values (5.39 ± 0.49‰, n = 27; 5.64 ± 0.48‰, n = 34; and 5.28 ± 0.34‰, n = 7, respectively), consistent with a mantle-derived origin for the primary magma(s) parental to the Talnakh intrusion. In contrast, a sulfide-bearing taxitic-textured troctolite from the basal part of intrusion has high δ18O (mean of 6.50‰, n = 3), indicating the possible involvement of a crustal component during the formation of sulfide-bearing taxitic-textured rocks. The Hf isotope compositions of zircon from different rocks of the Talnakh intrusion show significant variations, with ɛHf(t) values ranging from –3.2 to 9.8 for gabbrodiorite, from –4.3 to 11.6 for unmineralized layered-sequence gabbroic rocks, from 2.3 to 12 for mineralized ultramafic rocks, and from –3.5 to 8.8 for mineralized taxitic-textured rocks at the base of the intrusion. The significant range in the initial 176Hf/177Hf values is ascribed to interaction of distinct magma sources during formation of the Talnakh intrusion. These include (1) a juvenile source equivalent to the depleted mantle, (2) a subcontinental lithospheric source, and (3) a minor crustal component. Initial whole-rock Nd isotope compositions of the mineralized taxitic-textured rocks from the base of the intrusion (mean ɛNd(t) = –1.5 ± 1.8) differ from the other rocks, which have relatively restricted ranges in initial ɛNd (mean ɛNd = 0.9 ± 0.2). The major set of ɛNd values around 1.0 at Talnakh is attributed to limited crustal contamination, presumably in deep magma chambers, whereas the smaller set of negative ɛNd values in taxitic-textured rocks is consistent with greater involvement of a crustal component and reflects an interaction with the wall rocks during emplacement.