Importance Despite the COVID-19 pandemic’s effect on daily life, limited research exists on the prevalence and risk factors of suicidality and sadness among South Korean adolescents. Objectives To examine whether the observed sadness and suicidality in the early to middle periods of the COVID-19 pandemic differed from the expected level and to investigate changes in risk factors for sadness and suicidality. Design, Setting, and Participants This nationwide serial cross-sectional survey study used data on 1 109 776 Korean adolescents aged 13 to 18 years from the Korea Youth Risk Behavior Web-based Survey from 2005 to 2021. Exposure The COVID-19 pandemic. Main Outcomes and Measures The pattern of changes in the percentage or proportion of sadness or suicidality, as well as the risk factors for sadness or suicidality. The transitional effect of the COVID-19 pandemic was assessed using weighted odds ratios (wORs) or weighted beta coefficients with 95% CIs. Results Between 2005 and 2021, 1 109 776 adolescents (mean [SD] age, 15.0 [1.7] years; 51.5% male adolescents; and 51.7% in grades 7-9 and 48.3% in grades 10-12) were included in the Korea Youth Risk Behavior Web-based Survey. The slope of the long-term trends in sadness and suicidality decreased in the prepandemic period (sadness: from 37.8% [95% CI, 37.4%-38.2%] in 2005-2007 to 26.1% [95% CI, 25.9%-26.4%] in 2016-2019; suicidality: from 23.0% [95% CI, 22.7%-23.3%] in 2005-2007 to 12.3% [95% CI, 12.1%-12.5%] in 2016-2019), whereas the slope increased during the COVID-19 pandemic (sadness: from 25.0% [95% CI, 24.5%-25.6%] in 2020 to 26.6% [95% CI, 26.1%-27.1%] in 2021; trend difference in β, 0.249 [95% CI, 0.236-0.262]; suicidality: from 10.7% [95% CI, 10.3%-11.1%] in 2020 to 12.5% [95% CI, 12.1%-12.9%] in 2021; trend difference in β, 0.328 [95% CI, 0.312-0.344]). The trends presented a similar tendency in the subgroups according to sex, school grade, residential area, smoking status, and current alcohol use. Compared with the prepandemic period, the risk factors associated with sadness during the pandemic were younger age (wOR, 0.907; 95% CI, 0.881-0.933), female sex (wOR, 1.031; 95% CI, 1.001-1.062), urban residence (wOR, 1.120; 95% CI, 1.087-1.153), current smoking status (wOR, 1.134; 95% CI, 1.059-1.216), and current alcohol use (wOR, 1.051; 95% CI, 1.002-1.102). Female sex (wOR, 1.064; 95% CI, 1.021-1.109), urban residence (wOR, 1.117; 95% CI, 1.074-1.162), and low economic status (wOR, 1.286; 95% CI, 1.180-1.403) were the risk factors significantly associated with suicidality after the COVID-19 pandemic began. Conclusions and Relevance In this nationwide serial cross-sectional survey study of South Korean adolescents, the slope of the prevalence of sadness and suicidality increased during the COVID-19 pandemic after a decrease prior to the pandemic. The findings suggest that public health measures are needed to recognize vulnerable groups with risk factors and to prevent an increase in sadness and suicidality among adolescents during the COVID-19 pandemic.