Part of the Presidential Policy Directive 21 (PPD‐21) (PPD 2013) mandate includes evaluating safety, security, and safeguards (or nonproliferation) mechanisms traditionally implemented within the nuclear reactors, materials, and waste sector of critical infrastructure—including a complex, dynamic set of risks and threats within an all‐hazards approach. In response, research out of Sandia National Laboratories (Sandia) explores the ability of systems theory principles (hierarchy and emergence) and complex systems engineering concepts (multidomain interdependence) to better understand and address these risks and threats. This Sandia research explores the safety, safeguards, and security risks of three different nuclear sector‐related activities—spent nuclear fuel transportation, small modular reactors, and portable nuclear power reactors—to investigate the complex and dynamic risk related to the PPD‐21‐mandated all‐hazards approach. This research showed that a systems‐theoretic approach can better identify inter‐dependencies, conflicts, gaps, and leverage points across traditional safety, security, and safeguards hazard mitigation strategies in the nuclear reactors, materials, and waste sector. As a result, mitigation strategies from applying systems theoretic principles and complex systems engineering concepts can be (1) designed to better capture interdependencies, (2) implemented to better align with real‐world operational uncertainties, and (3) evaluated as a systems‐level whole to better identify, characterize, and manage PPD‐21's all hazards strategies.