We investigated distinctive factors associated with cognitive reserve (CR) based on education level. Among 1247 participants who underwent neuropsychological assessment, amyloid positron emission tomography, and brain magnetic resonance imaging, 336 participants with low education (≤6 years) and 697 with high education (≥12 years) were selected. CR was measured as the difference between the predicted and observed value of cognitive function based on cortical thickness. Multiple linear regression was conducted in each group after controlling for age and sex. In the low-education group, low literacy, long sleep duration(>8h/day), and diabetes were negatively associated with CR, whereas cognitive and physical activity were positively associated with CR. In the high-education group, cognitive activity was positively related to CR, whereas low literacy, long sleep duration (>8h/day), and depression were negatively related to CR. This study provides insights into different strategies for enhancing CR based on educational background. Factors associated with cognitive reserve (CR) varied according to the education level. Diabetes and physical activity were associated with CR in the low-education group. Depression was related to CR in the high-education group. Low literacy, sleep duration, and cognitive activity were associated with CR in both groups. Dementia-prevention strategies should be tailored according to educational level.