The dehydration of antigorite is an important reaction in subduction zones with implications on both geochemical and geophysical processes. In this experimental study we focus on the onset of antigorite dehydration and investigate various chemical and physical parameters as possible drivers for the fluid release. We performed hydrostatic and co-axial Griggs experiments on antigorite serpentinites with variable chemical composition and microstructures at high-pressure and high-temperature conditions across the antigorite dehydration (1.5 GPa, 620–670 °C). For these conditions, our thermodynamic models predict the formation of olivine from magnetite decomposition and partial dehydration of antigorite. Detailed analyses of the run products reveal limited magnetite decomposition. Antigorite dehydration is restricted to samples that have been deformed. Nano-sized olivine and orthopyroxene formed locally in oblique dehydration bands and exhibit neither a clear crystallographic preferred orientation nor a topotactic relation with precursor antigorite. We argue that limited local dehydration in our experiments is related to strain and variations in reaction kinetics. Systematic investigation excludes mineralogical and chemical heterogeneities, and temperature gradients as reaction driving potentials. The structural relation of the dehydration bands suggests deformation-related dehydration, which is supported by numerical simulations that couple reaction kinetics with mechanical work rate and self-consistently predict dehydration bands. In this scenario, strain concentration due to applied axial stress locally increases the internal energy of antigorite to reach the activation energy of the dehydration reaction, enabling dehydration. This study highlights the importance of coupled mechanical and chemical processes and provides a mechanistic framework for deformation-induced dehydration of antigorite.