Importance The mental health consequences of conflict and violence are wide-ranging and pervasive. Scalable interventions to address a range of mental health problems are needed. Objective To test the effectiveness of a multicomponent behavioral intervention delivered by lay health workers to adults with psychological distress in primary care settings. Design, Setting, and Participants A randomized clinical trial was conducted from November 1, 2014, through January 28, 2016, in 3 primary care centers in Peshawar, Pakistan, that included 346 adult primary care attendees with high levels of both psychological distress and functional impairment according to the 12-item General Health Questionnaire and the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0). Interventions Lay health workers administered 5 weekly 90-minute individual sessions that included empirically supported strategies of problem solving, behavioral activation, strengthening social support, and stress management. The control was enhanced usual care. Main Outcomes and Measures Primary outcomes, anxiety and depression symptoms, were independently measured at 3 months with the Hospital Anxiety and Depression Scale (HADS). Secondary outcomes were posttraumatic stress symptoms (Posttraumatic Stress Disorder Checklist for DSM-5), functional impairment (WHODAS 2.0), progress on problems for which the person sought help (Psychological Outcome Profiles), and symptoms of depressive disorder (9-item Patient Health Questionnaire). Results Among 346 patients (mean [SD] age, 33.0 [11.8] years; 78.9% women), 172 were randomly assigned to the intervention and 174 to enhanced usual care; among them, 146 and 160 completed the study, respectively. At baseline, the intervention and control groups had similar mean (SD) HADS scores on symptoms of anxiety (14.16 [3.17] vs 13.64 [3.20]; adjusted mean difference [AMD], 0.52; 95% CI, −0.22 to 1.27) and depression (12.67 [3.27] vs 12.49 [3.34]; AMD, 0.17, 95% CI, −0.54 to 0.89). After 3 months of treatment, the intervention group had significantly lower mean (SD) HADS scores than the control group for anxiety (7.25 [3.63] vs 10.03 [3.87]; AMD, −2.77; 95% CI, −3.56 to −1.98) and depression (6.30 [3.40] vs 9.27 [3.56]; AMD, −2.98; 95% CI, −3.74 to −2.22). At 3 months, there were also significant differences in scores of posttraumatic stress (AMD, −5.86; 95% CI, −8.53 to −3.19), functional impairment (AMD, −4.17; 95% CI, −5.84 to −2.51), problems for which the person sought help (AMD, −1.58; 95% CI, −2.40 to −0.77), and symptoms of depressive disorder (AMD, −3.41; 95% CI, −4.49 to −2.34). Conclusions and Relevance Among adults impaired by psychological distress in a conflict-affected area, lay health worker administration of a brief multicomponent intervention based on established behavioral strategies, compared with enhanced usual care, resulted in clinically significant reductions in anxiety and depressive symptoms at 3 months. Trial Registration anzctr.org.au Identifier: ACTRN12614001235695