IMPORTANCE: Psychological distress is characterized by anxiety and depressive symptoms. Although prior research has investigated the occurrence and factors associated with psychological distress in low- and middle-income countries, including those in Africa, these studies' findings are not very generalizable and have focused on different kinds of population groups. OBJECTIVE: To investigate the prevalence and characteristics (sociodemographic, psychosocial, and clinical) associated with psychological distress among African participants. DESIGN, SETTING, AND PARTICIPANTS: This case-control study analyzed data of participants in the Neuropsychiatric Genetics in African Populations-Psychosis (NeuroGAP-Psychosis) study, which recruited from general outpatient clinics in Eastern (Uganda, Kenya, and Ethiopia) and Southern (South Africa) Africa. Individuals who participated in the control group of NeuroGAP-Psychosis from 2018 to 2023 were analyzed as part of this study. Data were analyzed from May 2023 to January 2024. MAIN OUTCOMES AND MEASURES: The prevalence of psychological distress was determined using the Kessler Psychological Distress Scale (K10), which measures distress on a scale of 10 to 50, with higher scores indicating more distress. Participants from the NeuroGAP-Psychosis study were categorized into cases as mild (score of 20-24), moderate (score of 25-29), and severe (score of 30-50), and participants with scores less than 20 were considered controls. Factors that were associated with psychological distress were examined using binomial logistic regression. RESULTS: From the data on 21 308 participants, the mean (SD) age was 36.5 (11.8) years, and 12 096 participants (56.8%) were male. The majority of the participants were married or cohabiting (10 279 participants [48.2%]), most had attained secondary education as their highest form of learning (9133 participants [42.9%]), and most lived with their families (17 231 participants [80.9%]). The prevalence of mild, moderate, and severe psychological distress was 4.2% (869 participants), 1.5% (308 participants), and 0.8% (170 participants), respectively. There were 19 961 participants (93.7%) who served as controls. Binomial logistic regression analyses indicated that the independent associations of psychological distress were experience of traumatic events, substance use (alcohol, tobacco, or cannabis), the physical comorbidity of arthritis, chronic neck or back pain, and frequent or severe headaches. CONCLUSIONS AND RELEVANCE: In this case-control study among ethnically diverse African participants, psychological distress was associated with traumatic stress, substance use, and physical symptoms. These findings were observed to be consistent with previous research that emphasizes the importance of traumatic events as a factor associated with risk for psychopathology and notes the frequent co-occurrence of conditions such as physical symptoms, depression, and anxiety.