This systematic review synthesized literature on potential impacts of protracted isolation and other disruptions during the COVID-19 pandemic on deaths of despair (suicide, overdoses, and drug-related liver diseases). Five electronic databases were searched yielding 70 eligible articles. Extant evidence mostly from high-income countries indicates COVID-19-related disruption may not have influenced suicide rates so far, but there have been reports of increased drug-related and liver disease mortality. Minority groups and women were more vulnerable, indicating the need for stronger equity focus on pandemic recovery and resilience strategies. Further high-quality studies with longer-term follow-up, especially from low-income countries, will inform these strategies.