Reconstructing the paleofluid evolution in mature fault zones, which typically have complex structural architectures, is a challenging task because reactivation of pre-existing deformation structures and dissolution-reprecipitation processes are very abundant. Understanding why specific structural elements are preferentially mineralized and what are the factors leading to rapid fluid migration and accumulation, bears geological and economic implications, especially in seismically active fault zones. We studied the Compione Fault on the Tyrrhenian Sea side of the Northern Apennines orogenic wedge, Italy, which is a segment of the 30-km-long Northern Lunigiana high-angle extensional fault system still active today. The Compione Fault propagated from the metamorphic basement and accumulated about 1.5 km of displacement. We used structural, petrographic, isotopic, microthermometric, compositional, and organic matter analyses to constrain fluid and host rock properties during fault zone evolution. This approach allowed us to quantify the thermal anomaly in the fault zone and to infer the processes responsible for such a disequilibrium. Specifically, we show that in the fault process zone ahead of the upper fault tip, which is twice as wide as the damage zone, seismic pumping caused suprahydrostatic fluid pressures and that local dilation promoted the nucleation of a highly permeable mesh of conjugate extensional shear fractures hosting calc-silicate mineralization. The thermal difference between hydrothermal minerals in the conjugate fracture mesh and the host rock is 60–90 °C. The mineralizing fluids were deeply sourced from metamorphic reactions. Propagation of the upper fault tip caused process zone folding and incorporation into the fault damage zones. As the upper fault tip breached through shallower structural levels, it favored mixing between deep and meteoric fluids.