Introduction and Aim: Psychotic and mood disorders are associated with significant functional impairment, premature mortality, physical morbidity, and great social and economic burden. The aim of this study is to evaluate the effectiveness of psychosocial, psychological, and rehabilitative interventions implemented in an Italian psychiatric inpatient facility, with a focus on patients with schizophrenia spectrum versus those with mood disorders. Methods: A retrospective observational study was conducted in the psychiatric hospital Villa Maria Pia in Rome, Italy, during 2022. Patients with an established diagnosis of schizophrenia spectrum and mood disorder (ICD-9-CM) were assessed on admission (T0) and at the end of treatment (T1), using the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning (GAF). Interventions involved a multidisciplinary team and included individual and group activities. The t-test for independent samples was used to compare continuous variables between groups and Spearman correlation coefficient to calculate correlations between variables. Results: The study sample consisted of 141 patients, the majority of them being adults (51.3 years ± 12.4) men (F/M= 68/73). Among them, 85 patients (60.3%) actively engaged in psychosocial and rehabilitative interventions and, compared to non-participating individuals, they showed lower functioning and symptoms at discharge (delta GAF was significantly higher among patients who had taken part in the psychosocial activities, t = -2.095; p = 0.038). Considering the index computed (n of interventions/days of hospitalization), the number of psychosocial activities was positively correlated with the improvement in patients' functioning in the sample taking part in activities (r = 0.272, p = 0.012), especially with psychotherapy and support groups (r = 0.202, p = 0.017 and r = 0.188, p = 0.025, respectively). Splitting the total sample into schizophrenia-spectrum disorder (N = 37) and mood disorder (N = 48) groups, the positive correlations between GAF improvement and participation in psychosocial activities were confirmed only in the schizophrenia-spectrum group. These correlations were not significant for symptomatology (BPRS) either in the total or the individual group. Conclusion: Evidence from our study suggests that inpatient rehabilitation can be effective and useful for people with severe mental disorders. Further investigations are needed to better understand its effectiveness on improving quality of life and social functioning in the long term.