Low-cost interventions for adolescent depression and anxiety are needed in low-resource countries such as those in Sub-Saharan Africa. To assess whether Shamiri, a 4-week layperson-delivered group intervention that teaches growth mindset, gratitude, and value affirmation, can alleviate depression and anxiety symptoms in symptomatic Kenyan adolescents. This school-based randomized clinical trial included outcomes assessed at baseline, posttreatment, and 2-week and 7-month follow-up from 4 secondary schools in Nairobi and Kiambu County, Kenya. Adolescents aged 13 to 18 years with elevated symptoms on standardized depression or anxiety measures were eligible. Intent-to-treat analyses were used to analyze effects. Recruitment took place in June 2019; follow-up data were collected in August 2019 and February 2020. Adolescents were randomized to the Shamiri intervention or to a study skills control. All adolescents in both conditions met in groups (mean group size, 9) for 60 minutes per week for 4 weeks. Primary outcomes were depression (Patient Health Questionnaire-8 item) and anxiety (Generalized Anxiety Disorder-7 item) symptoms. Analyses of imputed data were hypothesized to reveal significant reductions in depression and anxiety symptoms for adolescents assigned to Shamiri compared with those in the study skills group. Of 413 adolescents, 205 (49.6%) were randomized to Shamiri and 208 (50.4%) to study skills. The mean (SD) age was 15.5 (1.2) years, and 268 (65.21%) were female. A total of 307 youths completed the 4-week intervention. Both Shamiri and study skills were rated highly useful (4.8/5.0) and reduced symptoms of depression and anxiety, but analyses with imputed data revealed that youths receiving Shamiri showed greater reductions in depressive symptoms at posttreatment (Cohen d = 0.35 [95% CI, 0.09-0.60]), 2-week follow-up (Cohen d = 0.28 [95% CI, 0.04-0.54]), and 7-month follow-up (Cohen d = 0.45 [95% CI, 0.19-0.71]) and greater reductions in anxiety symptoms at posttreatment (Cohen d = 0.37 [95% CI, 0.11-0.63]), 2-week follow-up (Cohen d = 0.26 [95% CI, -0.01 to 0.53]), and 7-month follow-up (Cohen d = 0.44 [95% CI, 0.18-0.71]). Both the Shamiri intervention and a study skills control group reduced depression and anxiety symptoms; the low-cost Shamiri intervention had a greater effect, with effects lasting at least 7 months. If attrition is reduced and the clinical significance of outcome differences is established, this kind of intervention may prove useful in other global settings where there are limited resources, mental illness stigma, or a shortage of professionals and limited access to mental health care. Pan-African Clinical Trials Registry Identifier: PACTR201906525818462.