Sphenoid sinus, located posterior to the nasal cavity, is difficult to reach for a surgery. Several operation procedures are available for sphenoidotomy, including endoscopic surgeries. Although the endoscopic sinus surgery is minimally invasive with low post-operative side effects, further optimization is required. Transnasal sphenoidotomy is a low invasive alternative to transethmoidal sphenoidotomy, but it still needs to be studied to understand its effects on the airflow pattern and the particle deposition. In this work, we simulated airflow and the micro-particle deposition in the nasal airway of a middle-aged man to investigate the change in particle deposition in the sphenoid sinus after virtual transnasal sphenoidotomy surgery. The results demonstrated that after transnasal sphenoidotomy, particle deposition in the targeted sphenoid sinus was an order of magnitude lower than that observed after virtual transethmoidal sphenoidotomy surgery. In addition, the diameter of the particles for the peak deposition fraction in the targeted sinus was shifted to smaller diameters after the transnasal sphenoidotomy surgery compared with that in the post-transethmoidal condition. These results suggest that the endoscopic transnasal sphenoidotomy can be a better procedure for sphenoid surgeries as it decreases the chance of bacterial contaminations and consequently lowers the surgical side effects and recovery time.