Background: Omega-3 polyunsaturated fatty acids (PUFA) may affect the risk of cognitive decline in older adults. Methods: Cross-sectional analysis was conducted among 720 (50.4% women) participants aged 68-92 years (mean age: 77.6, SD ±6.2) of the population-based KORA-Age study. Eicosapentaenoic acid and docosahexaenoic acid (omega-3 index) were measured in erythrocytes as a percentage of total fatty acids. The categories low (<5.7), intermediate (5.7-6.8), and high (>6.8) levels of the omega-3 index were built using tertiles. The association between cognitive status and omega-3 levels was assessed by logistic regression analyses with adjustments for important concurrent risk factors of cognitive decline. Results: In the sex- and age-adjusted model (model 1), subjects with a low omega-3 index were at a significantly higher risk for cognitive impairment (OR: 1.77, 95% CI: 1.15-2.73, p = 0.009). This association remained stable after further adjusting for educational level (model 2; OR: 1.75, 95% CI: 1.13-2.71, p = 0.01) and metabolic risk factors (model 3; OR: 1.77, 95% CI: 1.14-2.75, p = 0.01). After further controlling for affective disorders (model 4), the association did not attenuate (OR: 1.77, 95% CI: 1.14-2.76, p = 0.01). Conclusion: A robust association was found between low omega-3 levels and cognitive impairment in an elderly population. Further research is needed to understand the link between omega-3 PUFA and cognitive functioning.