Introduction/Objectives: The endoscopic approach to skull base lesions is widely regarded as less invasive and associated with reduced morbidity, offering favorable outcomes, particularly in terms of short-term quality of life (QOL). However, to date, long-term assessments of both nasal function and tumor-related QOL remain limited. To evaluate patients’ long-term nasal- and tumor-related QOL after endoscopic endonasal resection of pituitary tumors and to detect predictors for poor postoperative QOL. Study Design: This study was a prospective cohort study. Methods: All patients with pituitary adenomas who underwent trans-sphenoidal surgery at Tel Aviv Sourasky Medical Center between 2014 and 2021 were recruited. Recruited patients completed the Anterior Skull Base Disease-Specific QOL (ASBS-Q) questionnaire and the Sinonasal Outcome Test 22 (SNOT-22) questionnaire before surgery and 1, 2, and 3–5 years after surgery. Clinical data were collected and analyzed. Results: The study included 43 patients (18 women). No significant decrease was observed in tumor-related quality of life (QOL) scores, measured by ASBS-Q and SNOT-22, throughout the 5-year follow-up period. SNOT-22 score differences from the preoperative baseline at years 1, 3, and 5 were 0.81 [−4.84–6.58], 3.35 [−4.32–11.02], and 3.73 [−2.22–9.68], respectively, with no statistically significant changes. ASBS-Q scores similarly showed no significant changes over time. Subgroup analyses revealed that tumor characteristics (secreting vs. non-secreting, size), surgical factors (intraoperative cerebrospinal fluid leak, gross tumor resection, use of nasoseptal flap), and endocrine remission did not significantly impact QOL (p > 0.05 for all variables). Conclusions: Our study demonstrated that patients who underwent endoscopic pituitary lesion resection maintained high nasal- and tumor-related quality of life over a 5-year follow-up period. However, given the limitations of our study, further multi-center studies with larger patient populations are warranted to validate these results.