In this paper, we present a comprehensive defense framework for cyber-physical systems comprising proactive and reactive mechanisms in a multi-agent scenario. The scenario is compounded of three crazyflie nano quadcopters – open-source flying development platforms – connected to a centralized controller via radio communication operating in uncertain and adversarial environments. The proactive mechanism, based on the principles of moving target defense, utilizes a stochastic switching structure to dynamically and continuously alter the altitude of hovering of the agents to minimize the risk of attack while the attacker’s effect is modeled as time-varying and unknown. The reactive mechanism, on the other side, detects potentially attacked components, namely sensors and actuators, by leveraging online data to compute an integral Bellman error. The attack detection relies on the optimality property as well as on data measured along the trajectories of the system; when an attack is detected by an agent at a certain altitude of hovering, the information is shared with all agents via a centralized controller to classify the region as unsafe. The efficacy of the proposed defense framework is shown by experimental trials in different scenarios of cyber-physical attacks.