<p>With the progression of aging and population mobility in China, empty-nest older adults constitute a significant proportion of the elderly population. Compared with other groups, empty-nest older adults are more prone to depression. This study aims to investigate the prevalence of depression and its associated factors among rural empty-nest older adults in China, with a particular focus on gender differences. The findings are expected to provide a scientific basis for improving the mental health status of this population. This study utilized data from the 2018 Chinese Longitudinal Healthy Longevity Survey (CLHLS), focusing on rural empty-nest older adults as the target population. The chi-square test was employed to examine whether there were differences in the prevalence of depression across various subgroup variables. Binary logistic regression was used to identify factors associated with depression among the overall sample of rural empty-nest older adults, as well as to explore gender-based differences in these associations. The prevalence of depression among rural empty-nest older adults in China was 13.04%, with a significantly higher rate observed in females than in males (χ²= 22.492, <i>P</i> &lt; 0.001). Common risk factors for depression in both males and females included being without a spouse, having a low living standard, short sleep duration, and lack of social activities. Compared with males, being aged 70–79 years was a unique protective factor against depression in females, whereas poor self-rated health emerged as a specific risk factor for depression among the female population. There is a notable gender difference in the prevalence of depression among rural empty-nest older adults in China, with a higher incidence observed in females. Accordingly, government interventions should be tailored to address the specific factors associated with depression in different gender groups.</p>