Unraveling the time-space evolution ofMississippi Valley-type (MVT) hydrothermal systems is critically important for understanding ore genesis and exploration.We studied a complete mineral system fromconduit-filling to tail-end facies in the worldclass Sichuan–Yunnan–Guizhou triangle,South China, via field geology, mineralogy,fluid inclusions, and in situ sulfide S-Pb isotopes to propose an integrated model for theevolution of MVT hydrothermal systems.Geological mapping shows that the mineralization transitions from breccia pipe tostratabound style: high-grade ores occurmainly as open-space infill associated withF12 fault (fluid conduit), while low-gradeevaporite-related replacement ores developed distal from the fault. The δ34S value inhydrothermal sulfides shows a wide range(+3.6‰ to +27.9‰), with significant intragrain variation (up to +12.8‰), which suggests a mixture of 34S-rich sulfur producedby thermochemical sulfate reduction ofevaporite within the ore host and 32S-richsedimentary/diagenetic pyrite. In situ sulfidePb ratios decrease away from the F12 fault,which indicates that metals were sourcedfrom different degrees of mixing betweenthe Proterozoic metamorphic basementand wall rocks. Fluid-inclusion microthermometric data identify two distinct fluids:a hotter (>155 °C), more saline (>18 wt%NaCl equivalent), and metal-rich fluid with acooler (<90 °C), low-salinity (<4 wt% NaClequivalent), and reduced sulfur-rich fluid.The mixing of two fluids was responsible forprecipitating the high-grade ores near the F12fault, and the acid-producing (H+) processcreated new space for stratabound ore distalto the fault. This study highlights that fluidmixing is critical for efficient sulfide accumulation, and the metal zoning pattern providesguidelines for exploration.