The threat of attack faced by cyber-physical systems (CPSs), especially when they play a critical role in automating public infrastructure, has motivated research into a wide variety of attack defence mechanisms. Assessing their effectiveness is challenging, however, as realistic sets of attacks to test them against are not always available. In this paper, we propose smart fuzzing, an automated, machine learning guided technique for systematically finding ‘test suites’ of CPS network attacks, without requiring any expertise in the system’s control programs or physical processes. Our approach uses predictive machine learning models and metaheuristic search algorithms to guide the fuzzing of actuators so as to drive the CPS into different unsafe physical states. We demonstrate the efficacy of smart fuzzing by implementing it for two real-world CPS testbeds—a water purification plant and a water distribution system—finding attacks that drive them into 27 different unsafe states involving water flow, pressure, and tank levels, including six that were not covered by an established attack benchmark. Finally, we use our approach to test the effectiveness of an invariant-based defence system for the water treatment plant, finding two attacks that were not detected by its physical invariant checks, highlighting a potential weakness that could be exploited in certain conditions.