Background: An acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is difficult to achieve satisfactory results only with general drug therapy in clinic. The optimized comprehensive exercise prescription is a scientific intervention that has been used in the past in the care of chronic patients. However, the effectiveness of this intervention in patients with AECOPD has been rarely reported. Objective: To explore the effect of optimized comprehensive exercise prescription on rehabilitation effect, cardiopulmonary function, and short-term prognosis of patients with AECOPD. Methods: During February 2019 to August 2022, 140 patients with AECOPD cured in our hospital were randomly classified into control group (n=70) and study group (n=70). A routine intervention was provided to the control group, while a comprehensive exercise prescription intervention was provided to the study group. The efficacy of the different interventions, pulmonary function, life quality, severity of dyspnea, improvement of exercise ability and blood gas analysis were compared. Results: In the control and study groups, the total effective rate was 65.71% and 90.00% respectively. A better intervention efficacy was observed in the study group (P<0.05). The forced expiratory volume in the first second (FEV1), the expiratory flow at forced exhalation of 25%/75% vital capacity (FEF25%-75%) and the percentage of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) in the study group after the different interventions were higher (P<0.05). After the intervention, the St. George respiratory questionnaire (SGRQ) of patients lessened, and the SGRQ scores in the study group were lower (P<0.05). After the intervention, the dyspnea score lessened, and the dyspnea score of the study group was lower (P<0.05). After the intervention, the 6-minute walking distance (6MWD) of patients elevated, and the 6MWD in the study group was higher (P<0.05). After the intervention, the arterial partial pressure of oxygen (PaO2) elevated and the arterial partial pressure of carbon dioxide (PaCO2) lessened. The PaCO2 in the study group was lower, and PaO2 was higher (P<0.05). Conclusion: Optimized comprehensive exercise prescription can remarkably improve the exercise ability and life quality of patients with acute exacerbation of stable chronic obstructive pulmonary disease. In the meanwhile, it can also enhance the cardiopulmonary function of patients, improve short-term prognosis, and achieve good rehabilitation outcomes.