Recent events outlined the relevance of the interactions between industrial and natural hazards (NaTech) particularly for what concerns seismic risk. EU regulation, namely Directive 2012/18/EU, explicitly requires risk analysis for NaTech events. The development of a risk assessment methodology for major hazard industrial plants allows the individuation of the critical elements of a plant in seismic-prone areas. The implementation of smart technologies (sensors, actuators, innovative systems for seismic protection) to the critical elements allows for a relevant reduction of major hazards and related consequences. The “smart” application of NaTech management technologies, from early warning to active protection, allows to upgrade the safety conditions of existing industrial plants implemented as a retrofit solution, avoiding heavy and expensive structural actions. Furthermore, taking into account that the earthquake affects the entire plant and the safety systems (as extinguishing water supply and power lines) at the same time, smart technologies allow the simultaneous monitoring and control toward seismic events. Hence, it is evident that smart technologies can play a relevant role in NaTech management. Systems like EW and Active protection systems can be effectively used to reduce the seismic risk of a process plant.