There is growing evidence that the internet has beneficial effects on the mental health of middle-aged and older people (≥45 years), but the evidence is inconclusive, and the underlying mechanisms are less known.This study aims to explore the relationship between multidimensional (devices, frequency, and purpose) internet use and depression in middle-aged and elderly Chinese, as well as the mediating effect of social participation. Moreover, this study will explore the moderating effect of the regional informatization development level (RIDL) on the relationships between individual internet use, social participation, and depression.Data on 17,676 participants aged 45 years or older were obtained from the China Health and Retirement Longitudinal Study (CHARLS) 2018 data set. The 10-item Center for Epidemiologic Studies Depression Scale (CES-D-10) was used to identify the presence of depression. Logistic regression was used to explore the relationship between each dimension of internet use and depression. Multiple linear regression was used to explore the mediating effect of social participation and the moderating effect of the RIDL.The results showed that 28.33% (5008/17,676) of the total population had depression. In terms of regional subgroups, respondents living in the western region exhibited the highest proportion of depression (2041/5884, 34.69%). Internet use was negatively associated with depression (odds ratio 0.613, 95% CI 0.542-0.692; P<.001). Various dimensions of internet use positively contributed to individual social participation and reduced individual depression (devices: β=-.170, 95% CI -0.209 to -0.127; frequency: β=-.065, 95% CI -0.081 to -0.047; and purpose: β=-.043, 95% CI -0.053 to -0.031). In addition, the RIDL weakened the relationship between individual-level internet use and social participation (internet use: F74.12,9.82=7.55, P<.001; devices: F51.65/9.88=5.23, P=.005; frequency: F66.74/10.08=6.62, P=.001; and purpose: F66.52/9.78=6.80, P=.001), and negatively moderated the relationship between the frequency of internet use and depression (frequency: F662.67/188.79=3.51, P=.03).This study found that different dimensions of internet use are associated with lower levels of depression. Social participation partially mediates the association between multidimensional internet use and depression in the eastern, central, and western regions, respectively. Additionally, the RIDL helps individuals further their internet use and social participation, reducing the impact of depression. However, this effect weakens sequentially from the western region to the central region and then to the eastern region.©Xiwang Du, Jiazhi Liao, Qing Ye, Hong Wu. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.08.2023.