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The Niukutou Pb-Zn deposit is typical of skarn deposits in the Qimantagh metallogenic belt (QMB) in the East Kunlun Mountains. In this study, based on detailed petrographical observations, electron microprobe analyses (EMPAs), and laser-ablation–inductively coupled plasma–mass spectrometry (LA-ICP-MS) analyses, we report the major and trace element compositions of the typical skarn mineral assemblages (garnet, pyroxene, ilvaite, epidote, and chlorite) in this deposit. Three hydrothermal mineralization stages with different mineral assemblages of the prograde metamorphic phase were determined, which were distributed from the inside to the outside of the ore-forming rock mass. Grt1+Px1 (Stage 1), Grt2+Px2 (Stage 2), and Px3 (Stage 3) were distinguished in the Niukutou deposit. Furthermore, the ilvaites in the retrograde metamorphic phase can be divided into three stages, namely Ilv1, Ilv2, and Ilv3. The ore-forming fluid in Stage 1 exhibited high ∑REE, U, and Nd concentrations and δEu, δCe, and LREE/HREE values, which were likely derived from a magmatic–hydrothermal source and formed at high temperatures, high <i>f</i>O₂ values, and mildly acidic pH conditions, and probably experienced diffusive metasomatism in a closed system with low water/rock ratios. In Stages 2 and 3, the ore-forming exhibited lower ∑REE, U, and Nd concentrations and δEu, δCe, and LREE/HREE values, with high Mn content that had likely experienced infiltrative metasomatism in an open system with high water/rock ratios. From Ilv1 to Ilv3, the δEu and U contents decreased, whereas the Mn content increased, indicating that the oxygen fugacity of mineralization was in decline. The ore-forming fluid evolution of the Niukutou deposit can be characterized as follows: from Stage 1 to Stage 3, the hydrothermal fluid migrated from the deep plutons to the shallow skarn and marble; the environment altered from the high <i>f</i>O₂ and temperature conditions to low <i>f</i>O₂ and temperature values, and the pH and Mn contents increased. The fluids contained considerable metal ore-forming materials that were favorable for the enrichment and precipitation of the Fe content. In the retrograde metamorphic phase, with the decrease in oxygen fugacity (from Ilv1 to Ilv3), the temperature and oxygen fugacity of the theore-forming fluid environment decreased, ultimately becoming conducive to the dissolution and precipitation of Pb and Zn elements.