Abstract Background Nasoseptal flaps (NSF), perfused by the posterior septal artery (PSA), are heavily utilized in endonasal skull base surgery (ESBS). We use indocyanine green (ICG) fluorescence angiography to assess PSA perfusion. Methods A prospective study of adult ESBS patients assessed PSA perfusion using intraoperative ICG. PSA ICG fluorescence intensities (FIs) were quantified. Factors analyzed included demographics, comorbidities, prior sinonasal surgery, surgical approach, concurrent septoplasty, NSF harvest timing, and flap-related complications. t-Tests compared significant ICG baseline differences and changes from baseline. ICG enhancement was compared with postoperative magnetic resonance imaging (MRI). Results A total of 54 patients were studied. Of these, 35 NSFs were harvested, while the remaining 19 underwent cuts for rescue flaps. Mean PSA FI changed from baseline 118.1 ± 28.6 to 114.4 ± 32.3 following reconstruction. Tobacco users had lower baseline FI compared with non-tobacco users (78.3 ± 62.8 vs. 118.4 ± 29.1, p = 0.003). Transpterygoid approaches showed greater decrease from baseline (−25.8 ± 58.9 vs. −3.8 ± 32.1, p = 0.035) than transsphenoidal. No other studied factors, including revision case, timing of flap harvest, flap side, division of palatosphenoidal artery, or concurrent septoplasty, had a significant influence on ICG intensity. In total, 34 of 35 NSFs were viable. ICG fluorescence had a 100% sensitivity, 0% specificity, and 96.6% positive predictive value (PPV) for NSF viability, while MRI enhancement had a 100% sensitivity, 100% specificity, and 100% PPV for NSF viability. Conclusion ICG angiography may provide an intraoperative assessment of flap viability with comparable PPV as postoperative MRI. Tobacco use and transpterygoid approaches may be associated with decreased PSA perfusion.