Background A bloodless surgical field coupled with stable hemodynamics is pivotal for successful surgical intervention, especially in endonasal surgeries. This study investigates the effect of intranasal desmopressin spray in reducing surgical bleeding and on hemodynamics compared with topical epinephrine in patients scheduled for endonasal dacryocystorhinostomy (DCR). Methods Fifty-two patients were randomly allocated into two groups in this double-blind clinical study: Desmopressin group (n=26): patients received two puffs of desmopressin acetate 10 μg/puff in the side of the nasal cavity ipsilateral to the obstructed lacrimal duct (20 µg totally) 60 min before the surgery. Epinephrine group (n=26): patients received topical 1 : 100 000 epinephrine in the nasal cavity ipsilateral to the obstructed lacrimal duct via 3 soaked packs placed in the middle meatus for 5 min after induction of general anesthesia and before the start of surgery. Results The median clarity of the surgical field based on the BOEZAART grading system was significantly clearer in the desmopressin group compared with epinephrine group. The duration of surgery was significantly shorter in the desmopressin group (66.92±5.04 min) compared with epinephrine group (71.73±5.45 min). Mean arterial blood pressure (MABP) and heart rate (HR) were statistically significant higher in epinephrine group compared to the desmopressin group at 2 and 5 min after topical epinephrine compared with desmopressin group. Conclusion Pre-emptive 20 ug single dose of intranasal desmopressin provides a clear surgical field with no hemodynamics effects compared with topical epinephrine in patients undergoing endonasal dacryocystorhinostomy. Clinicaltrial.gov (ref: NCT05507476, date of registration: 18-8–2022).