Objective Social isolation is a global health issue that affects older adults throughout their lives. This study aimed to identify the factors associated with social isolation in older adults. Design Systematic review and meta-analysis. Setting and Participants Adults aged 60 years and older. Methods We searched for observational studies without language restrictions in 11 databases from inception to August 2022. Pooled odds ratio (OR) and 95% CI were calculated using the R software (version 4.2.1). The modified Newcastle-Ottawa Scale was used to evaluate the risk of bias. Results Eighteen factors were grouped into 5 themes. The following 13 factors were statistically significant: (1) demographics theme: aged 80 years and older (OR: 2.41; 95% CI: 1.20–4.85), less than or equal to a high school degree (OR: 1.68; 95% CI: 1.44–1.97), smoking (OR: 1.43; 95% CI: 1.18–1.73), and male (OR: 1.38; 95% CI: 1.01–1.89); (2) environment theme: low social support (OR: 7.77; 95% CI: 3.45–17.50) and no homeownership (OR: 1.38; 95% CI: 1.25–1.51); (3) role theme: no social participation (OR: 3.18; 95% CI: 1.30–7.80) and no spouse (OR: 2.61; 95% CI: 1.37–4.99); (4) physical health: hearing loss (OR: 2.78; 95% CI: 1.54–5.01), activities of daily living impairment (OR: 2.38; 95% CI: 1.57–3.61), and poor health status (OR: 1.52; 95% CI: 1.32–1.74); and (5) mental health: cognitive decline (OR: 1.85; 95% CI: 1.40–2.45) and depression (OR: 1.72; 95% CI: 1.21–2.44). Conclusions and Implications Social isolation in older adults is associated with various factors. Hence, focused intervention should be adopted for older adults. In addition, further longitudinal studies are required to confirm a direct link between multiple factors and social isolation.