Objective: To investigate the clinical efficacy of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for treating malignant peritoneal mesothelioma (MPM) and to assess the impact of this approach on patient prognosis. Methods: A retrospective analysis of 44 patients with MPM was performed. The control group (CNG, N = 23) was treated with CRS combined with postoperative intraperitoneal (IP) chemotherapy, while the observation group (OG, N = 21) was treated with CRS combined with HIPEC. The treatment efficacy, volume of blood loss, operation time, postoperative length of stay, and 3-year survival rate (SR) were compared, and the factors affecting the prognosis of MPM patients were analyzed by multivariate analysis. Results: The OG showed decreased volume of blood loss and operation time, while also showing increased overall treatment efficacy compared with the CNG. The SR in the OG was 65.22% compared with a rate of 33.33% in the CNG, and the 3-year SR in the OG was significantly higher than that in the CNG. Multivariate analysis revealed that tumor-node-metastasis (TNM) stage, Eastern Cooperative Oncology Group (ECOG) score, and treatment modality were independent risk factors for the prognosis of MPM patients. Conclusion: CRS combined with HIPEC for MPM has a favorable treatment efficacy and prolongs the survival of MPM patients. Additionally, TNM stage, ECOG score, and treatment modality are independent risk factors for the prognosis of MPM patients.