Drawing from the National Survey on Drug Use and Health (NSDUH; N = 611,880), a nationally representative survey of U.S. adolescents and adults, we assess age, period, and cohort trends in mood disorders and suicide-related outcomes since the mid-2000s. Rates of major depressive episode in the last year increased 52% 2005–2017 (from 8.7% to 13.2%) among adolescents aged 12 to 17 and 63% 2009–2017 (from 8.1% to 13.2%) among young adults 18–25. Serious psychological distress in the last month and suicide-related outcomes (suicidal ideation, plans, attempts, and deaths by suicide) in the last year also increased among young adults 18–25 from 2008–2017 (with a 71% increase in serious psychological distress), with less consistent and weaker increases among adults ages 26 and over. Hierarchical linear modeling analyses separating the effects of age, period, and birth cohort suggest the trends among adults are primarily due to cohort, with a steady rise in mood disorder and suicide-related outcomes between cohorts born from the early 1980s (Millennials) to the late 1990s (iGen). Cultural trends contributing to an increase in mood disorders and suicidal thoughts and behaviors since the mid-2000s, including the rise of electronic communication and digital media and declines in sleep duration, may have had a larger impact on younger people, creating a cohort effect.