The Perceived Stress Scale (PSS) is a widely used measure of psychological stress and has demonstrated robust psychometric properties in adult populations. However, its validity and reliability in younger populations has not been investigated. This study aimed to confirm the factor structure and estimate the internal consistency of the 10-item PSS among youth with mental illness; assess its validity; and, investigate whether the PSS can differentiate between youth with internalizing and externalizing disorders. Data come from a clinical sample of 67 youth currently receiving services for their mental health. Confirmatory factor analysis was used to replicate the factor structure of the PSS. Correlations were used to examine construct validity and Mann–Whitney U tests to compare PSS scores across mental illnesses. The two-factor (helplessness and self-efficacy) structure of the PSS was confirmed and internal consistency reliability was high (α = 0.88). There was solid evidence of convergent validity with measures of family functioning (r = 0.34), disability (r = 0.72), health-related quality of life (r = 0.37 to 0.60), and self-concept (r = 0.30 to 0.74). There was no difference in PSS scores across age or sex. Higher PSS scores were found for youth with internalizing disorders, but no difference for those with versus without externalizing disorders. Because of the relatively small sample size, further research is needed in larger and more diverse samples, as well as additional research to determine clinically relevant thresholds within the PSS to facilitate its routine use in clinical and public health settings.