We previously published a unique methodology for quantifying human velopharyngeal mucosal surface topography and found increased mucosal surface roughness in patients with obstructive sleep apnea (OSA). In fluid mechanics, surface roughness is associated with increased frictional pressure losses and resistance. This study used computational fluid dynamics (CFD) to analyze the mechanistic effect of different levels of mucosal surface roughness on velopharyngeal airflow. Reconstructed velopharyngeal models from OSA and control subjects were modified, giving each model three levels of roughness, quantified by the curvature-based surface roughness index (CBSRI_0.6) (range 24.8–68.6 mm⁻¹). CFD using the k-ω shear stress transport turbulence model was performed (unidirectional, inspiratory, steady-state, 15l/min volumetric flow rate), and the effects of roughness on flow velocity, intraluminal pressure, wall shear stress, and velopharyngeal resistance ( R_v) were examined. Across all models, increasing roughness increased maximum flow velocity, wall shear stress, and flow disruption while decreasing intraluminal pressures. Linear mixed effects modeling demonstrated a log-linear relationship between CBSRI_0.6 and R_v, with a common slope (log( R_v)/CBSRI_0.6) of 0.0079 [95% confidence interval (CI) 0.0015–0.0143; P = 0.019] for all subjects, equating to a 1.9-fold increase in R_v when roughness increased from control to OSA levels. At any fixed CBSRI_0.6, the estimated difference in log( R_v) between OSA and control models was 0.9382 (95% CI 0.0032–1.8732; P = 0.049), equating to an 8.7-fold increase in R_v. This study supports the hypothesis that increasing mucosal surface roughness increases velopharyngeal airway resistance, particularly for anatomically narrower OSA airways, and may thus contribute to increased vulnerability to upper airway collapse in patients with OSA. NEW & NOTEWORTHY Increased mucosal surface roughness in the velopharynx of patients with obstructive sleep apnea (OSA) has recently been identified, but its role in OSA pathogenesis is unknown. This is the first study to model the impact of increased roughness on airflow mechanics in the velopharynx. We report that increasing roughness significantly affects airflow, increasing velopharyngeal resistance and potentially increasing the vulnerability to upper airway collapse, particularly in those patients with an already compromised anatomy.