Background: Opioid abuse is a public health crisis and the perioperative period can be a time of first opioid exposure. Little is known about postoperative pain management after endoscopic skull base surgery (ESBS). Methods: This investigation was a single-institution, longitudinal, prospective cohort study of adult patients undergoing ESBS between November 2019 and March 2020. Participants completed preoperative questionnaires and were contacted every 48 hours postoperatively to quantify pain and opioid consumption. Results: A total of 33 patients were enrolled and 28 of 33 patients (85%) underwent ESBS for sellar pathology. Mean total morphine milligram equivalents (MME) consumed was 381.9 ± 476.0. History of a headache disorder (p = 0.025) and previous opioid use within 60 days preoperatively (p < 0.001) were significantly associated with greater opioid use. Mean duration of opioid use was 6.7 ± 5.1 (range, 0-20) days. Headache disorder (p = 0.01), depression (p = 0.03), anxiety (p = 0.03), age ≤46 years (p = 0.029), and previous opioid use (p = 0.008) were all associated with longer mean opioid use. Patients with headache disorder also reported higher mean postoperative pain scores. Fewer than half of the participants required opioids by postoperative day 8. Prescription of nonsteroidal anti-inflammatory drugs at discharge was significantly associated with less outpatient opioid use (p = 0.032). At 2-month follow-up, 37% of patients reported keeping excess opioids. Conclusion: After ESBS, greater total opioid use was significantly associated with history of headaches and previous opioid use within 60 days. Overall, opioid use declined among all patients in the postoperative period, but several factors may contribute to longer duration of use.