In low-resource settings, valid mental health screening tools for non-specialists can be used to identify patients with psychiatric disorders in need of critical mental health care. The Mental Wellness Tool-13 (mwTool-13) is a 13-item screener for identifying adults at risk for common mental disorders (CMDs) alcohol-use disorders (AUDs), substance-use disorders (SUD), severe mental disorders (SMDs), and suicide risk (SR). The mwTool-13 is administered in two steps, specifically, only those who endorse any of the initial three questions receive the remaining ten questions. We evaluated the performance of mwTool-13 in South Africa against a diagnostic gold standard. We recruited a targeted, gender-balanced sample of adults, aged ≥18 years at primary and tertiary healthcare facilities in Eastern Cape Province. Of the 1885 participants, the prevalence of CMD, AUD, SMD, SR, and SUD was 24.4%, 9.5%, 8.1%, 6.0%, and 1.6%, respectively. The mwTool-13 yielded high sensitivities for CMD, SMD, and SR, but sub-optimal sensitivities for AUD and SUD (56.7% and 64.5%, respectively). Including a single AUD question in the initial question set improved the tool’s performance in identifying AUD and SUD (sensitivity > 70%), while maintaining brevity, face-validity, and simplicity in the South African setting.