Mental disorders (MD) among children and adolescents are usually associated with over-activation of stress response pathways and poor mood state, quality of life and wellbeing. Arts interventions may help to reduce biological stress and improve psychological outcomes in this population. We determined the effects of four arts activities on salivary cortisol, immunoglobulin-A, mood state, quality of life, and wellbeing in young people with MD. Forty-two in- and out-patients in child and adolescent psychiatry (aged 12–18) were engaged in short-term arts activities (singing, textile design, drama, clownery) conducted by professional artists, delivered through five consecutive 90-minute daily sessions in one week. Cortisol, immunoglobulin-A, and mood state were assessed daily pre-post interventions. Quality of life and well-being were measured pre-post 5-day-interventions. Over five days, the arts activities apart from singing significantly affected reductions in cortisol (textile design − 0.81, 95% CI -1.48 to -0.14; drama − 0.76, 95% CI -1.28 to -0.24; clownery − 0.74, 95% CI -1.47 to -0.01). Textile design led to significant improvement in alertness (4.08; 95% CI 0.77 to 7.39), and singing (2.20, 95% CI -0.55 to 4.94) and textile design (2.89, 95% CI -0.39 to 6.18) tended to influence a positive change in mood. Quality of life measurements increased significantly in singing (5.49, 95% CI 1.05 to 9.92); well-being and immunoglobulin-A showed no significant changes. Arts activities may provide a complementary solution to reduce stress and improve mood state in young people with MD. Further investigation is needed to confirm the results and explain the differences in psycho-biological responses.