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Loneliness and social isolation have been identified as critical global health issues in the aftermath of the coronavirus disease 2019 (COVID-19) crisis. While there is robust scientific evidence demonstrating the impact of loneliness and social isolation on health outcomes and mortality, there are fundamental issues to resolve so that health authorities, decision makers, and practitioners worldwide are informed and aligned with the latest evidence. Three priority actions are posited to achieve a wider and more substantial impact on loneliness and social isolation. They are 1) strengthening the evidence base; 2) adopting a whole-of-systems approach; 3) developing policy support for governments worldwide. These priority actions are essential to reduce the pervasive impact of loneliness and social isolation as social determinants of health.