The railway transport system is critical infrastructure that is exposed to numerous man-made and natural threats, thus protecting this physical asset is imperative. Cyber security, privacy, and dependability (SPD) are also important, as the railway operation relies on cyber-physical systems (CPS) systems. This work presents SPD-Safe—an administration framework for railway CPS, leveraging artificial intelligence for monitoring and managing the system in real-time. The network layer protections integrated provide the core security properties of confidentiality, integrity, and authentication, along with energy-aware secure routing and authorization. The effectiveness in mitigating attacks and the efficiency under normal operation are assessed through simulations with the average delay in real equipment being 0.2–0.6 s. SPD metrics are incorporated together with safety semantics for the application environment. Considering an intelligent transportation scenario, SPD-Safe is deployed on railway critical infrastructure, safeguarding one outdoor setting on the railway’s tracks and one in-carriage setting on a freight train that contains dangerous cargo. As demonstrated, SPD-Safe provides higher security and scalability, while enhancing safety response procedures. Nonetheless, emergence response operations require a seamless interoperation of the railway system with emergency authorities’ equipment (e.g., drones). Therefore, a secure integration with external systems is considered as future work.