The global COVID-19 response focused heavily on nonpharmaceutical interventions (NPIs) until vaccines became available. Even where vaccination coverage is low, over time governments have become increasingly reluctant to use NPIs. Inequities in vaccine and treatment accessibility and coverage, differences in vaccine effectiveness, waning immunity, and immune-escape variants of concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reinforce the long-term need for mitigation. Initially, the concept of NPIs, and mitigation more broadly, was focused on prevention of SARS-CoV-2 transmission; however, mitigation can and has done more than prevent transmission. It has been used to address the clinical dimensions of the pandemic as well. The authors propose an expanded conceptualization of mitigation that encompasses a continuum of community and clinical mitigation measures that can help reduce infection, illness, and death from COVID-19. It can further help governments balance these efforts and address the disruptions in essential health services, increased violence, adverse mental health outcomes, and orphanhood precipitated by the pandemic and by NPIs themselves. The COVID-19 pandemic response revealed the benefits of a holistic and layered mitigation approach to public health emergencies from the outset. Lessons learned can inform the next phases of the current pandemic response and planning for future public health emergencies.