Objectives. To describe the recent global prevalence of e-cigarette use and to investigate its associated factors among youths aged 12 to 16 years in 68 countries and territories (hereafter "countries"). Methods. We analyzed 485 746 youths aged 12 to 16 years from the population-based cross-sectional Global Youth Tobacco Survey conducted in 67 countries between 2012 and 2019 and the 2019 National Youth Tobacco Survey in the United States. We defined past-30-day e-cigarette use as using e-cigarettes on 1 or more days during the past 30 days. Results. The global prevalence of past-30-day e-cigarette use among youths was 9.2%, ranging from 1.9% in Kazakhstan to 33.2% in Guam. Maternal smoking (adjusted odds ratio [AOR] = 1.40; 95% confidence interval [CI] = 1.29, 1.52), paternal smoking (AOR = 1.13; 95% CI = 1.07, 1.19), secondhand smoke exposure (AOR = 1.74; 95% CI = 1.64, 1.84), youth cigarette smoking (AOR = 7.18; 95% CI = 6.84, 7.54), and youth other tobacco use (AOR = 3.88; 95% CI = 3.62, 4.15) were positively associated with e-cigarette use. Conclusions. E-cigarette use was moderately frequent among youths aged 12 to 16 years globally. Several important factors were associated with youth e-cigarette use. Public Health Implications. Our findings highlight the need for countries worldwide to develop policies to address e-cigarette use among youths. (Am J Public Health. 2022;112(4):650-661. https://doi.org/10.2105/AJPH.2021.306686).