Background: Endoscopic transsphenoidal surgery is the most common technique for the resection of pituitary adenoma. Data on factors associated with extended hospital stay after this surgery are limited. We aimed to characterize the relationship between preoperative medications and the risk of prolonged postoperative length of stay after this procedure. Methods: This single-center, retrospective cohort study included all adult patients scheduled for transsphenoidal pituitary surgery from 1 July 2016 to 31 December 2019. Anatomical Therapeutic Chemical codes were used to identify patients’ preoperative medications. The primary outcome was a prolonged postoperative hospital length of stay. Secondary outcomes included unplanned admission to the Intensive Care Unit, and in-hospital and one-year mortality. We developed a descriptive logistic model that included preoperative medications, obesity and age. Results: Median postoperative length of stay was 3 days for the 704 analyzed patients. Patients taking ATC-H drugs were at an increased risk of prolonged length of stay (OR 1.56, 95% CI 1.26–1.95, p < 0.001). No association was found between preoperative ATC-H medication and unplanned ICU admission or in-hospital mortality. Patients with multiple preoperative ATC-H medications had a significantly higher mean LOS (5.4 ± 7.6 days) and one-year mortality (p < 0.02). Conclusions: Clinicians should be aware of the possible vulnerability of patients taking systemic hormones preoperatively. Future studies should test this medication-based approach on endoscopic transsphenoidal pituitary surgery populations from different hospitals and countries.