Background: Despite the significant psychiatric effects of the COVID-19 pandemic, theres limited data on the prevalence and risk factors of depression and suicide attempts among South Korean adults. Methods: A nationwide cross-sectional study using the Korea National Health and Nutrition Examination Survey (KNHANES) data from 1998 to 2021 was conducted. Changes in prevalence and risk factors for depression and suicide attempts were assessed using weighted odds ratios or weighted beta coefficients.Results: During the observation period (1998-2021), the prevalence of depression increased in the overall population; however, no significant surge was found regarding the COVID-19 pandemic, from 2.78% (95% CI, 2.41-3.15) in 1998-2005-4.96% (4.32-5.61) in 2020 and 5.06% (4.43-5.69) in 2021. However, immediately after the onset of the pandemic, younger ages, male sex, urban residence, higher education, and high economic status became significant vulnerable factors compared to pre-pandemic periods. The prevalence of suicide attempts remained stable, and there was no notable surge specifically related to the COVID-19 pandemic, from 0.23% (95% CI, 0.18-0.28) in 1998-2005-0.45% (0.25-0.66) in 2020 and 0.42% (0.24-0.60) in 2021. Furthermore, no distinct vulnerable factors associated with suicide attempts have been identified. Conclusion: Through this nationwide serial cross-sectional survey study, we emphasized the need for under-standing the differential impacts of global crises, such as COVID-19, across varied population subgroups, thereby highlighting the importance of specific and targeted mental health support strategies.