Abstract Objectives In recent years, the transnasal endoscopic method for transsphenoidal pituitary tumor resection (eTSR), alongside the conventional sublabial microscopic transsphenoidal resection (mTSR) method, has gained popularity due to advancements in imaging and instrumentation. The current study sought to elucidate whether the trend toward eTSR was associated with changes in clinical outcomes at a single institution's multidisciplinary pituitary surgery program. Setting and Participants The Virginia Commonwealth University (VCU) Brain Tumor Database was queried for patients who underwent either transnasal or sublabial pituitary tumor resection of pituitary tumors between 2009 and 2021. Design Clinical outcomes were compared between the two groups. Main Outcome Measures Surgical outcomes like estimated blood loss (EBL), cerebrospinal fluid (CSF) leak rates, hospital length of stay (LOS), and extent of resection were studied. Results A total of 93 patients (57 mTSR, 36 eTSR) underwent review, revealing that mTSR was associated with a higher average intraoperative blood loss (310.5 ± 48.6 mL) than eTSR (160.0 ± 30.7 mL; p = 0.012). eTSR demonstrated an elevated intraoperative CSF leak incidence (36.1 vs. 15.8%; p = 0.043), but no difference in postoperative CSF leak requiring intervention. Hospital LOS and extent of resection showed no significant differences between the approaches. Conclusion This single-institution, retrospective study suggests that, in experienced hands, both eTSR and mTSR approaches are effective with comparable risk profiles. The approach may be best determined by the surgical team's evaluation of the tumor's imaging features, paying attention to the patient's preoperative hematologic status due to the greater propensity for blood loss with the microscopic approach.