Objectives. To investigate the long-term (12- and 24-month) impact of an economic empowerment intervention on HIV risk behaviors and mental health among school-going adolescent girls in Uganda. Methods. A total of 1260 girls aged 14 to 17 years were randomized at the school level to (1) standard health and sex education (controls; n = 408 students; n = 16 schools), (2) 1-to-1 matched savings youth development account (YDA; n = 471 students; n = 16 schools), or (3) combination intervention (YDA and multiple family group [YDA+MFG]; n = 15 schools; n = 381 students). Mixed-effects models were fitted. Results. YDA and YDA+MFG girls had significantly lower depressive symptoms and better self-concept than controls at 24 months. Only YDA+MFG girls had significantly lower hopelessness levels than controls. There were no significant study group differences at 12 and 24 months for sexual risk-taking behavior and attitudes. There was no significant difference between YDA and YDA+MFG groups for all outcomes. Conclusions. Providing YDA and MFG can positively improve adolescent girls' mental health, but our analyses showed no significant differences across groups on sexual risk-taking behaviors. Future studies may consider replicating these interventions and analyses in older populations, including those transitioning into young adults. Trial Registration. ClinicalTrials.gov Identifier: NCT03307226. (Am J Public Health. 2023;113(3):306-315. https://doi.org/10.2105/10.2105/AJPH.2022.307169).