Background <p>Hyperhomocysteinemia, an elevation of plasma homocysteine levels, has been implicated in multiple diseases, yet its causal role remains debated. This umbrella review systematically evaluated and graded the evidence from published systematic reviews and meta-analyses on associations between hyperhomocysteinemia and diverse health outcomes.</p> Methods <p>We searched Medline, Embase, and Web of Science up to March 5, 2025. Eligible studies were systematic reviews and meta-analyses of observational studies reporting associations between hyperhomocysteinemia and any health outcome. Methodological quality was assessed using AMSTAR-2, and the certainty of evidence was graded using GRADE.</p> Results <p>A total of 104 meta-analyses including 2,110 studies and 953,793 participants were analyzed, covering 126 outcomes. Eighty-three percent of outcomes showed significant associations with hyperhomocysteinemia. Nine outcomes were supported by high, 18 by moderate, 73 by low, and 26 by very low certainty of evidence. High-certainty evidence supported associations between hyperhomocysteinemia and increased risks of stroke, intracerebral haemorrhage, fracture (hip and total), and chronic kidney disease. Moderate-certainty evidence linked hyperhomocysteinemia to dementia, Alzheimer’s disease, mortality, and selected cardiovascular and pregnancy outcomes. Most meta-analyses were of low or critically low methodological quality.</p> Conclusions <p>Across nearly one million participants, hyperhomocysteinemia was consistently associated with adverse health outcomes, particularly vascular, neurological, skeletal, and renal conditions. While causality cannot be inferred, the evidence supports hyperhomocysteinemia as a potentially modifiable risk factor meriting targeted preventive and interventional research.</p> Protocol registration <p><a href="https://osf.io/dezms">https://osf.io/dezms</a></p>