The energy revolution is primarily driven by the adoption of advanced communication technologies that allow for the digitization of power grids. With the confluence of Information Technology (IT) and Operational Technology (OT), energy systems are entering the larger world of Cyber-Physical Systems (CPS). Cyber threats are expected to grow as the attack surface expands, posing a significant operational risk to any cyber-physical system, including the power grid. Substations are the electricity transmission systems’ most critical assets. Substation outages caused by cyber-attacks produce widespread power outages impacting thousands of consumers. To plan and prepare for such rare yet high-impact occurrences, this paper proposes an integrated defense-in-depth framework for power transmission systems to reduce the risk of cyber-induced substation failures. The inherent resilience of physical power systems assesses cyber-attacks’ impact on critical substations. The presented approach integrates the physical implications of substation failures with cyber vulnerabilities to analyze cyber-physical risks holistically.