OBJECTIVE: The aim of this study was to examine the validity, reliability and responsiveness of common generic paediatric health-related quality of life (HRQoL) instruments in children and adolescents with mental health challenges. METHODS: Participants were a subset of the Australian Paediatric Multi-Instrument Comparison (P-MIC) study and comprised 1013 children aged 4-18 years with attention-deficit/hyperactivity disorder (ADHD) (n = 533), or anxiety and/or depression (n = 480). Participants completed an online survey including a range of generic paediatric HRQoL instruments (PedsQL, EQ-5D-Y-3L, EQ-5D-Y-5L, CHU9D) and mental health symptom measures (SDQ, SWAN, RCADS-25). A subset of participants also completed the HUI3 and AQoL-6D. The psychometric performance of each HRQoL instrument was assessed regarding acceptability/feasibility; floor/ceiling effects; convergent validity; known-group validity; responsiveness and test-retest reliability. RESULTS: The PedsQL, CHU9D, EQ-5D-Y-3L and EQ-5D-Y-5L showed similarly good performance for acceptability/feasibility, known-group validity and convergent validity. The CHU9D and PedsQL showed no floor or ceiling effects and fair-good test-retest reliability. Test-retest reliability was lower for the EQ-5D-Y-3L and EQ-5D-Y-5L. The EQ-5D-Y-3L showed the highest ceiling effects, but was the top performing instrument alongside the CHU9D on responsiveness to improvements in health status, followed by the PedsQL. The AQoL-6D and HUI3 showed good acceptability/feasibility, no floor or ceiling effects, and good convergent validity, yet poorer performance on known-group validity. Responsiveness and test-retest reliability were not able to be assessed for these two instruments. In subgroup analyses, performance was similar for all instruments for acceptability/feasibility, known-group and convergent validity, however, relative strengths and weaknesses for each instrument were noted for ceiling effects, responsiveness and test-retest reliability. In sensitivity analyses using utility scores, performance regarding known-group and convergent validity worsened slightly for the EQ-5D-Y-3L and CHU9D, though improved slightly for the HUI3 and AQoL-6D. CONCLUSIONS: While each instrument showed strong performance in some areas, careful consideration of the choice of instrument is advised, as this may differ dependent on the intended use of the instrument, and the age, gender and type of mental health condition of the population in which the instrument is being used. TRIAL REGISTRATION: ANZCTR-ACTRN12621000657820.