Background: Advances in cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC) have improved outcomes for selected patients with peritoneal surface malignancies (PSMs). Methods: This retrospective study analyzed 743 PSM patients treated at Fondazione Policlinico Universitario Agostino Gemelli from January 2016 to February 2024. The primary aim was to assess median overall survival (mOS), median disease-free survival (mDFS), and median progression-free survival (mPFS) stratified by tumor origin. Secondary outcomes examined the role of diagnostic laparoscopy in the management of PSMs and intra- and postoperative complications’ rates. Results: A total of 1113 procedures were performed: 389 CRS, 370 PIPAC, and 354 diagnostic laparoscopies. Colorectal cancer was the predominant indication for CRS (52.4%), with a mOS of 52 months and mDFS of 22 months. Patients affected by gastric cancer undergoing CRS had a mOS of 18 months and a mDFS of 13 months, while PIPAC yielded a mOS of 9 months and a mPFS of 4 months. Among patients with pseudomyxoma peritonei undergoing CRS, the 5-year DFS rate was 64.1%, and OS rate was 89%. Patients affected by mesothelioma and treated with CRS exhibited a median OS of 43 months and a DFS of 26 months. Pancreatic and hepatobiliary cancers were treated with PIPAC, with a respective mOS of 12 and 8 months. Postoperative complications occurred in 12.6% of CRS, 3.2% of PIPAC, and 1.7% of diagnostic laparoscopies. High peritoneal cancer index (PCI), gastric resection, and blood loss over 500 mL were identified as risk factors for major complications in a multivariate analysis. Conclusions: Developing a highly experienced multidisciplinary team is crucial for delivering tailored treatment strategies which aim to achieve optimal oncological outcomes while preserving patients’ quality of life.