Abstract: Objective To explore the clinical efficacy of a progressive resistance respiratory comprehensive rehabilitation program in patients with post-stroke depression(PSD). Methods A total of 60 PSD patients who were admitted to Xuzhou Rehabilitation Hospital from September 2022 to January 2024 were selected and their clinical data were collected for analysis. The patients were randomly divided into two groups (n=30): an observation group and a control group. The control group received conventional rehabilitation treatment, while the observation group underwent the progressive resistance respiratory comprehensive rehabilitation program in addition to the conventional rehabilitation treatment. Both groups were subject to interventions for four weeks. Then, both groups were compared for respiratory muscle function maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP), anxiety and depression scale (SAS and SDS) scores, 6-minute walking test distance, autonomic function indicators resting heart rate (HRrest), peak heart rate (HRpeak), heart rate recovery 1 minute after exercise (HRR1), resting systolic/diastolic blood pressure (SBPrest and DBPrest), and peak systolic/diastolic blood pressure (SBPpeak and DBPpeak), and modified Barthel index (MBI) scores before and after the intervention. Results After four weeks of intervention, the observation group showed longer 6-minute walking distance, higher MIP and MEP than the control group (P<0.05). The SAS and SDS scores in the observation group decreased, but the MBI scores increased, compared with those in the control group (P<0.05). The observation group also showed increases in HRR1, and decreases in HRrest, HRpeak, and SBPrest, compared with the control group (P<0.05). Conclusions The progressive resistance respiratory comprehensive rehabilitation program can effectively improve respiratory muscle strength, correct autonomic dysfunction, enhance exercise capacity, and improve activities of daily living in PSD patients. This program holds clinical value in enhancing the quality of life of patients.