The Xikuangshan antimony (Sb) deposit is the world’s largest known Sb deposit. Due to the lack of suitable minerals for reliable high-precision radiometric dating, it remains difficult to determine the exact age of Sb mineralization in this deposit. Here, we report the first LA-MC-ICP-MS U-Pb ages of syn-stibnite calcite from this deposit. The dating results indicate the presence of at least two stages of Sb mineralization in the Xikuangshan ore district. The calcite-stibnite veins in the Daocaowan ore block probably formed during the Paleocene (58.1 ± 0.9 Ma), representing an early stage of Sb mineralization, while the quartz-stibnite vein in the Feishuiyan ore block probably formed during the Eocene (50.4 ± 4.4 Ma, 50.4 ± 5.0 Ma, and 51.9 ± 1.6 Ma), representing a late stage of Sb mineralization. The new calcite U-Pb ages are significantly younger than the calcite Sm-Nd ages (124.1 ± 3.7 Ma, 155.5 ± 1.1 Ma) reported by previous researchers. We suggest that Sb mineralization of the South China antimony metallogenic belt may be related to tectono-thermal events during Paleogene, possibly linked to high heat flow during the subduction (ca. 60–40 Ma) of the Pacific Plate beneath the Eurasian Plate and/or the Indo–Asian Collision (began at ca. 61 Ma). The young in situ U-Pb ages of calcite challenge the idea of late Mesozoic Sb mineralization in the South China antimony metallogenic belt, suggesting the requirement for more high-precision dating studies.