The novel severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19), has presented healthcare delivery challenges the world has never encountered before. Healthcare and its practitioners, while finding themselves in difficult situations, must still care for patients with emergent needs and ensure the safety and well-being of all patients and staff. At Mayo Clinic, effective navigation of the dynamic and complex situation created by COVID-19 required unique multidisciplinary collaborations to design and implement solutions quickly. Frontline care providers and staff of ancillary services and other critical healthcare functions partnered with the Department of Management Engineering and Consulting (ME&C) team to organise and re-engineer operations to iteratively adapt to the dynamic ‘new normal’. Health systems engineers (HSEs) and project managers (PMs) accelerated the implementation of innovative interventions by leveraging advanced engineering and consulting frameworks, models and methods. Utilising a patient and staff-centric systems approach to align electronic systems, operational processes, staffing resources and organisational infrastructure has been invaluable for speed and effectiveness. Harnessing the promise of digital technology and advanced analytics was imperative and set the stage for a broader set of possibilities to transform healthcare. These possibilities include scaling of consumerfocused virtual services in multiple and unfamiliar settings, new assets that could be reused for future emergencies, accelerating the implementation of time-sensitive solutions, applied analytics and modelling to predict clinical, financial and community impacts and reimaging the healthcare supply chain. As more has been learned about the trajectory and management of COVID-19, the need to rapidly evolve and pivot interventions for short-, medium-, and long-term applications continues. This article addresses the unique contributions of ME&C during the COVID-19 crisis and the results-oriented collaborations with staff in critical business functions. We believe that the experiences, outcomes and lessons learned through this journey are broadly transferable to other healthcare and nonhealthcare organisations.