Abstract Loneliness and social isolation are important public health concerns due to their associations with a range of health outcomes. However, it is difficult to ascertain whether any effects are biased by confounding and reverse causation. We use a triangulation approach combining observational, sibling control, and Mendelian Randomisation analyses (a genetically informed analysis), to draw robust conclusions about these relationships. Using a combination of UK Biobank data (N = 8,004 to 414,432) and genome-wide association studies (N = 17,526 to 2,083,151), we examine relationships between loneliness and social isolation and outcomes related to physical health, mental health and wellbeing and general health (e.g., multimorbidity capturing both mental and physical health). We find evidence for effects of loneliness and social isolation on poorer mental health and wellbeing and of loneliness on poorer general health. We do not find evidence of effects on specific physical health outcomes; however, these effects cannot definitively be ruled out.