BACKGROUND We aimed to investigate the prevalence trends and explore the influencing factors of post-stroke depression based on the National Health and Nutrition Examination Survey (NHANES) database, including data from 2005 to 2018. MATERIAL AND METHODS A total of 1298 patients with stroke were included in this study. Multivariate logistic regression analysis was performed to select influencing factors. Subgroup analysis was conducted based on different populations. The odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS The prevalence of post-stroke depression was 16.35% in 2005 and 23.29% in 2018, and presented a linear upward trend by year (F=195.00, P<0.001) from 2005 to 2018. Age (≥60 years vs <60 years; OR=0.40; 95% CI, 0.30-0.54), sex (female vs male; OR=1.37; 95% CI, 1.02-1.84), education level (junior middle school or below vs college or above; OR=0.64; 95% CI, 0.46-0.90), annual household income (≥$20,000 vs <$20,000; OR=0.60; 95% CI, 0.45-0.80), and sleep disorders (sleep disorders vs no sleep disorders; OR=4.07; 95% CI, 3.01-5.49) were associated with the risk of post-stroke depression. The age-based subgroup analysis showed that sex and education level were not influencing factors of post-stroke depression in patients ≥60 years, and education level was not related to the risk of post-stroke depression among men in the sex-based analysis. CONCLUSIONS Stroke patients with sleep disorders, age <60 years, and female sex may have an increased risk of post-stroke depression.