Homocysteine (Hcy) has been reported to be associated with cognitive decline in numerous studies, but evidence regarding differences across study designs and populations remains limited. Therefore, we conducted a meta-analysis to evaluate the association between Hcy and cognitive decline according to study type and patient subgroups. A total of 56 studies were included after the full-text review of articles identified from 3 databases: Cochrane library, Embase and Pubmed. The outcome of interest was incidence of cognitive decline. Hcy was classified as either a continuous or categorical variable, and the impact of elevated level of Hcy on cognitive decline was estimated using meta-analysis. Subgroup analyses were also conducted based on baseline patient characteristics. In continuous analyses, the pooled odds ratios (ORs) of increasing Hcy level were 1.11 (95% CI, 1.07–1.14) for cross-sectional studies, 1.28 (95% CI, 0.98–1.67) for case-control studies, and 1.04 (95% CI, 1.02–1.05) for cohort studies. In categorical analyses, elevated Hcy (>15) was linked to greater risk of cognitive decline, and this association was more pronounced in cross-sectional (OR, 2.72; 95% CI, 1.85–4.01) and case-control studies (OR, 2.44; 95% CI, 1.33–4.49). Subgroup analysis also showed that patients aged ≥60 years had a higher risk of cognitive decline. In conclusion, elevated Hcy levels are associated with an increased risk of cognitive decline, especially among the elderly, highlighting the need for preventive and management strategies.