Skarn Cu deposits are one of most important deposit-type in Middle-Lower Yangtze River region, eastern China, but skarn formation process remains unclear. Mineralogical, morphological and in situ geochemical data from the skarn stage of Tongguanshan skarn Cu deposit in Tongling region are systemically investigated, to reveal the timing, physical-chemical conditions, and fluid evolution during the skarn formation. The Tongguanshan garnets can be identified homogeneous and unzoned early generation garnet (GrtI), and oscillating zoned late generation garnet (GrtII) with the Fe-rich core (GrtII-Fe) and Al-rich edge (GrtII-Al). Garnet U–Pb dating results show that the Tongguanshan Cu mineralization was formed in 145.6 ± 4.4 Ma. In situ elemental composition results of the garnet samples indicate that they belong to grossular-andradite solid solution series, and are a magmatic-hydrothermal origin. The distinctly geochemical characteristics (e.g., Sn and U contents, (La/Yb)N, δEu and Y/Ho values) reveal that the physiochemical conditions from GrtI to GrtII-Fe, and GrtII-Fe to GrtII-Al stages in the Tongguanshan skarn formation were an increase and a decrease of fluid salinity and oxygen fugacity, closed to open and then to closed of fluid environment, and neutral-weakly acidic to acidic and acidic to neutral-weakly acidic of fluid pH, respectively. A comprehensive discriminant analysis indicates a fluid boiling occurred in the GrtI to GrtII-Fe stage of the Tongguanshan skarn Cu deposit, and there is little or no external fluid mixed during the skarn stage.