Rising concerns about social isolation and loneliness globally have highlighted the need for a greater understanding of their mental and physical health implications. Robust evidence documents social connection factors as independent predictors of mental and physical health, with some of the strongest evidence on mortality. Although most data are observational, evidence points to directionality of effects, plausible pathways, and in some cases a causal link between social connection and later health outcomes. Societal trends across several indicators reveal increasing rates of those who lack social connection, and a significant portion of the population reporting loneliness. The scientific study on social isolation and loneliness has substantially extended over the past two decades, particularly since 2020; however, its relevance to health and mortality remains underappreciated by the public. Despite the breadth of evidence, several challenges remain, including the need for a common language to reconcile the diverse relevant terms across scientific disciplines, consistent multi-factorial measurement to assess risk, and effective solutions to prevent and mitigate risk. The urgency for future health is underscored by the potentially longer-term consequences of the COVID-19 pandemic, and the role of digital technologies in societal shifts, that could contribute to further declines in social, mental and physical health. To reverse these trends and meet these challenges, recommendations are offered to more comprehensively address gaps in our understanding, and to foster social connection and address social isolation and loneliness.