One recent study showed that atomoxetine-oxybutynin combination (AOC) use is effective in reducing obstructive sleep apnea (OSA) severity. We used a nationwide database to examine the association between AOC use and the risk of OSA incidence. This retrospective cohort study used Taiwan’s National Health Insurance Research Database between the years 2000 and 2015. The patients who used atomoxetine or oxybutynin were included as an exposed cohort. The exposed and unexposed groups were selected in a ratio of 1:3 with sex, age, and index year matching. We used the multivariate Cox proportional regression model to evaluate the association between AOC use and the risk of an incident diagnosis of OSA. The incidence rates of OSA in the exposed cohort (N = 8940) and the unexposed cohort (N = 26,820), were 21.92 and 22.93 per 100,000 person-years, respectively. The adjusted hazard ratio of oxybutynin use only and AOC with a treatment duration of ≥ 366 days were 0.307 (95% CI 0.204–0.995, P = 0.045) and 0.299 (95% CI 0.102–0.933, P = 0.002), respectively. Long-term atomoxetine-oxybutynin combination therapy may be beneficial to reduce the risk of obstructive sleep apnea. Further studies to examine these mechanisms are warranted.