Mental disorders are highly prevalent worldwide and have a high impact on daily functioning. Exercise therapy was found to improve health of individuals with physical and mental disorders. This study aims to investigate the effectiveness of an Adapted Personalized Motor Activity (AMPA) in improving health in individuals with physical and mental disorders. Forty-three patients affected by both mental and chronic nontransmissible conditions were randomly assigned to intervention group (AMPA intervention) and control group (no intervention). Perceived physical and mental health were assessed using the Short Form 12 (SF-12) questionaries. Moreover, subjects underwent an accurate medical screening process, complete clinical evaluation, body composition evaluation, and cardiopulmonary assessment. Repeated Measurement Analysis of the Variance (RM-ANOVA) was used to compare any changes in health and physiological parameters in-between groups. AMPA group showed a statistically significant improvement in both perceived mental and physical health. Moreover, Body Mass Index (BMI), glycolipid profile, aerobic functional capacity and cardiopulmonary parameters improved significantly among individuals from the intervention group compared with the individuals from the control group. AMPA may be considered a possible intervention to improve health in individuals suffering from multiple physical and mental disorders. Future studies should examine the effectiveness in larger and heterogeneous sample of chronically ill patients and the long-term effect of AMPA.