Summary Earthquakes induced by fluid extraction from deep underground reservoirs are not well understood in rocks that are deforming plastically. The problem grows in importance when seismicity risk mitigation strategies, such as gas injection into a depleting hydrocarbon reservoir, attempt to reverse the declining pressure trend of a poromechanical system deforming irreversibly. This is the case at the Groningen gas field and similar fields worldwide. Poroplasticity associated with half a century of seasonally fluctuating gas production makes it challenging to predict Groningen’s state, especially with hundreds of faults compartmentalizing the reservoir. We provide new insights into the role of plasticity in depletion-induced seismicity and its mitigation via injection. The irreversibility of plastic deformation is key to predicting stress and fault stability when the pressure trend is reversed by fluid injection. The elastic deformation assumption predicts unrealistically high Coulomb failure stresses on the faults, implying a higher risk of induced seismicity than possible under plastic deformation. The inaccuracy in the elastic model’s predicted stress cannot be discerned from the reservoir pressure or subsidence measurements in the field. Therefore, rock’s plasticity must be considered in assessing and mitigating the risk of induced seismicity. The probability distribution of the change in Coulomb failure stress over 115 faults in the field reveals a multimodal shape that emerges from the stabilization and destabilization of different faults depending on the fault’s geometry and position relative to the wells.