Background <p>Diet was a potentially modifiable factor in the prevention of depression. We aimed to investigate associations of an overall plant-based diet index (PDI), a healthful PDI (hPDI), and an unhealthful PDI (uPDI) with the prevalence of depression. We hypothesized that plant-based diets especially the hPDI may be associated with lower depression, whereas uPDI would increase the depression.</p> Methods <p>This is a cross-sectional study using data from the US National Health and Nutrition Examination Survey 2005–2018. Diet was assessed by 24-hour recalls. Depression was measured using the Patient Health Questionnaire-9 (PHQ-9). Odds ratios (ORs) and percentage changes (%) were calculated by logistic regression and linear regression, respectively.</p> Results <p>Among the 31,622 participants aged 20 years or older, the age-standardized prevalence of major depression (PHQ-9 score ≥ 10) was 8.8% (<i>n</i> = 2,744). The overall PDI was not associated with odds of depression (OR comparing extreme quintiles 0.84, 95% confidence interval [CI]: 0.66–1.07; <i>p</i>_trend=0.168), whereas it was associated with lower PHQ-9 scores in multiple linear regression (<i>β</i>=-0.07, 95%CI: -0.13, -0.02, <i>p</i>_trend=0.045). Participants with higher hPDI scores had lower odds of depression (OR = 0.69, 95%CI: 0.55, 0.87, <i>p</i>_trend<i>=</i>0.007) and lower PHQ-9 scores (<i>β</i>=-0.07, 95%CI: -0.14, 0.00, <i>p</i>_trend<i>=</i>0.013). Conversely, higher uPDI scores were positively associated with prevalence of depression (OR = 1.78, 95%CI: 1.44–2.20, <i>p</i>_trend<i>&lt;</i>0.001) and PHQ-9 scores (<i>β</i> = 0.19, 95%CI: 0.14, 0.24, <i>p</i>_trend<i>&lt;</i>0.001).</p> Conclusions <p>Plant-based diets, especially when they are enriched with healthier plant foods, may be beneficial for primary prevention of depression. However, plant-based diets that emphasize less healthy plant foods are associated with higher depression levels among US adults.</p>