Purpose This article aims to identify patient- and surgery-related factors that could predict the development of postoperative central diabetes insipidus (DI). Methods This is a retrospective case-control study conducted at a single-institution tertiary referral center. Patients undergoing endoscopic endonasal skull base surgery for pituitary adenoma between November 2018 and April 2023 were recruited. The main outcome measures collected include age, gender, comorbidities, tumor type, postoperative DI, intraoperative and postoperative cerebrospinal fluid (CSF) leak, flow of CSF leak, number of layers required for repair, the use of nasal packing, and hospital length of stay. Results A total of 20 patients developed DI postoperatively. Patients' demographic and comorbidity profile did not correlate with DI development. The encounter of an intraoperative CSF leak was correlated with postop DI (chi-square (1) = 18.35, p < 0.001) with a relative risk (RR) of 2.7 (confidence interval [CI] = 1.37-5.28). The use of nasal packs was also correlated with postop DI (chi-square (1) = 10.17, p = 0.001) with a RR of 1.8 (CI = 1.15-2.87). Defects requiring a two or more layers for reconstruction also correlated with postop DI compared to single layer repairs (chi-square (1) = 12.15, p < 0.001) irrelevant of the materials used. Development of DI postop correlated with an increased hospital length of stay ( t (64) = -3.35, p = 0.001). Conclusion The physician should be careful when evaluating patients with pituitary adenomas in the postoperative period, particularly those with intraoperative CSF leak, nasal packing, and those who underwent multilayer reconstruction of the surgical defect.