The challenges brought on by the COVID-19 pandemic have been far-reaching and impactful in unforeseen ways. During 2020, regional emergency response efforts for “normal” national disasters were executed while enveloped in the grip of the global Coronavirus pandemic. Hurricanes, floods, wildfires, and earthquakes happen most every year, but not under the hampering restrictions of a global pandemic. Federal and regional response efforts were severely impacted. These efforts normally require the utilization of federal, state, and local Emergency Operations Centers (EOCs) and other incident response centers which are normally staffed with representatives from numerous organizations working together in close proximity for long durations. The pandemic significantly limited the “in-person” interaction between response individuals and organizations, requiring innovative solutions to managing incidents in the pandemic setting. Agencies were forced to quickly adapt and leverage new mechanisms and partnerships to facilitate a timely response. The salient lessons learned in standing up and running an effective EOC (in-person and virtual) for natural disasters during the pandemic are directly relatable to the nuclear power and nuclear security enterprises. The need to stand up an EOC in response to an incident that impacts at-risk radiological or nuclear material is a rare occurrence. Regardless, the preparation for such an event is paramount as a flawed multi-agency response operation threatens continuity of operations of our critical infrastructure. This paper will explore the relevant lessons learned in EOC operations during the COVID-19 era and how they can be applied to radiological and nuclear incidents.