Volcanoes are unstable structures that deform laterally and frequently experience mass wasting events. Hydrothermal alteration is often invoked as a mechanism that contributes significantly to volcano instability. We present a study that combines laboratory experiments, geophysical data, and large-scale numerical modeling to better understand the influence of alteration on volcano stability, using La Soufrière de Guadeloupe (Eastern Caribbean) as a case study. Laboratory experiments on variably altered (advanced argillic alteration) blocks show that uniaxial compressive strength, Young’s modulus, and cohesion decrease as a function of increasing alteration, but that the internal friction angle does not change systematically. Simplified volcano cross sections were prepared (a homogenous volcano, a volcano containing the alteration zone identified by a recent electrical survey, and a volcano with an artificially enlarged area of alteration) and mechanical properties were assigned to zones corresponding to unaltered and altered rock. Numerical modeling performed on these cross sections, using a hydro-thermo-mechanical modeling code, show (a) the importance of using upscaled values in large-scale models and (b) that alteration significantly increases volcano deformation and collapse volume. Finally, we combined published muon tomography data with our laboratory data to create a 3D strength map, exposing a low-strength zone beneath the southern flank of the volcano coincident with the hydrothermal system. We conclude that hydrothermal alteration decreases volcano stability and thus expedites volcano spreading and increases the likelihood of mass wasting events and associated volcanic hazards. Hydrothermal alteration, and its evolution, should therefore be monitored at active volcanoes worldwide.