Importance: Loneliness has been associated with adverse health outcomes. However, few studies have evaluated its comparative effects on distinct health outcomes. Objective: The primary objective was to evaluate the comparative effects of loneliness on multiple health outcomes. The literature was qualitatively reviewed to identify risk factors associated with loneliness, explore mechanisms, and discuss potential evidence-based interventions for targeting loneliness. Data Sources: A systematic review and meta-analysis of studies were conducted to examine the association between loneliness and health outcomes. We searched the databases Ovid MEDLINE/PubMed, Embase, and PsycINFO from inception to April/01/2019 for relevant peer-reviewed publications. Study Selection: We selected studies that measured the association between subjective ratings of loneliness (i.e., UCLA Loneliness Scale or de Jong Gierveld Loneliness Scale) and one or more health outcome(s). Only validated measurement scales for health outcomes were used. Data Extraction and Synthesis: Data was extracted by four independent reviewers using a standardized data extraction form. A total of 114 identified studies were systematically evaluated to extract study characteristics, risk of bias, and loneliness-health associations required for the calculation of pooled effects (i.e., correlations). Main Outcome(s) and Measures: Loneliness and health outcomes were measured. Health outcomes were broadly defined to include measures of mental health (i.e., depression, anxiety, suicidality, general mental health), general health (i.e., overall self-rated health), well-being (i.e., quality of life, life satisfaction), physical health (i.e., functional disability), sleep, and cognition. Results: Loneliness had medium to large effects on all health outcomes, with the largest effects on mental health and overall well-being. No significant effects of age, health condition, or stigma were observed. However, we observed a significant effect of gender on the association between loneliness and cognition (i.e., more pronounced in studies with a greater proportion of males). We also observed a significant effect of geographical distribution on the associations between loneliness and overall well-being, sleep, and cognition (i.e., lower among European nations and higher among Asian nations). Conclusions and Relevance: Loneliness is associated with adverse effects on health, particularly mental health outcomes. Future research should explore the potential moderating effects of gender and geographical distribution. From a public health perspective, the adequate training of health care providers (HCPs) to perceive, detect, and respond to loneliness among patients should be prioritized. Funding Statement: The authors stated: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interests: Roger S. McIntyre is a consultant to speak on behalf of, and/or has received research support from Lundbeck, Janssen, Shire, Purdue, Pfizer, Otsuka, Allergan, Takeda, Neurocrine, Sunovion, Stanley Medical Research Institute, and CIHR/GACD/Chinese National Natural Research Foundation. All other authors have no conflicts of interest to disclose. Ethics Approval Statement: The current systematic review and meta-analysis adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement for transparent and comprehensive reporting of study methods and results.