Quantifying lithospheric strength is essential to better understand seismicity in continental regions. We estimate differential stresses and principal stress orientations driving rapid slip (~10 mm/yr) on the active Mai’iu low-angle normal fault (dipping 15–24° at the Earth’s surface) in Papua New Guinea. The fault’s mafic footwall hosts a well-preserved sequence of mylonite, foliated cataclasite, ultracataclasite and gouge. In these fault rocks, we combine stress inversion of fault-slip data and paleostress analysis of syntectonically emplaced calcite veins with microstructural and clumped-isotope geothermometry to constrain a syn-exhumational sequence of deformation stresses and temperatures, and to construct a stress profile through the exhumed footwall of the Mai’iu fault. This includes: 1) at ~12–20 km depth (T≈275–370°C), mylonites accommodated slip on the Mai’iu fault at low differential stresses (>25–135 MPa) before being overprinted by localized brittle deformation at shallower depths; 2) at ~6–12 km depth (T≈130–275°C) differential stresses in the foliated cataclasites and ultracataclasites were high enough (>150 MPa) to drive slip on a mid-crustal portion of the fault (dipping 30–40°), and to trigger brittle yielding of mafic footwall rocks in a zone of mixed-mode seismic/aseismic slip; and 3) at the shallowest crustal levels (T<150°C) on the most poorly oriented part of the Mai’iu fault (dipping ~20–24°), slip occurred on frictionally weak clay-rich gouges (μ≈0.15–0.38). Subvertical σ1 and subhorizontal σ3 parallel to the extension direction, with σ1≈σ2 (constriction), reflect vertical unloading and 3-D bending stresses during rolling-hinge style flexure of the footwall.