Stress-management interventions have been integrated into treatments for people with mental disorders. Nevertheless, most studies on these interventions have been conducted on patients with schizophrenia in Western countries, and limited studies have used objective measurements of stress. We developed a group-based, four-session stress-management (S-Manage) program for people with mental disorders, consisting of two major components: psychoeducation and relaxation practice. This single-group, pretest-posttest, quasi-experimental study was undertaken to test the initial effects and determine the effect sizes of the program. A convenience sample of 55 inpatients were recruited from a mental health ward at a tertiary hospital in Singapore. Self-report questionnaires and physiological measures of stress (skin temperature and salivary immunoglobulin A [SIgA]) were used for data collection. Data were analyzed by descriptive statistics and repeated-measures analysis of variance. Most participants were Singaporean, female, single, and employed. Diagnoses included schizophrenia, depression, bipolar disorder, anxiety disorder, and mixed diagnoses. All received standard care provided by the hospital. Participants had significant reductions in objective stress, measured by skin temperature (effect size = 0.54) and SIgA (effect size = 0.16), and subjective stress (effect size = 0.16) as well as improved psychological health (effect size = 0.40) in response to the intervention. This study provides preliminary evidence to support the positive effects of the S-Manage program on people with mental disorders. Future studies should further test the efficacy of the program using more rigorous methods such as randomized controlled trial and multicenter study.