Fluid-triggered mineral reactions in fault rocks may result in significant fault weakening by reduction of the friction coefficient value, particularly in the case of the formation of phyllosilicate minerals. Here, we document an excellent example of fault weakening controlled by complex chemo-mechanical feedback processes in a low-angle normal fault on the island of Serifos (Western Cyclades, Greece). Within and several tens of meters below the studied fault zone, a reaction front developed between dolomite-calcite mylonites and quartzite mylonite layers, triggered by fluid-assisted nucleation of talc. The talc formation facilitated domino boudinage of these quartzite mylonites, which, under ongoing frictional deformation, increased the permeability of the fault zone and, hence, facilitated additional influx of fluid associated with massive talc formation. Continuing deformation was strongly localized in these talc-rich layers, resulting in the progressive development of a low-angle normal fault at the brittle-ductile transition zone. Associated with another pulse of fluid influx, a late-stage static tremolite growth outlasted the deformation. In this paper, we set up a new chemo-mechanical model for strain softening and address the complex question of relative timing and coupling of mineral reactions and deformation mechanisms between the quartzite boudins and the dolomite-calcite marble host in a well-constrained tectono-metamorphic frame.