Background: Postoperative atrial fibrillation (POAF) is a common complication that has shown conflicting results regarding sex differences. The potential effect of age on this association has not been adequately explored. We hypothesized that younger males would have a higher risk of POAF than females and that this difference would vary by age group. Methods: In this observational cohort study, we enrolled consecutive patients who underwent non-cardiac surgery between January 2011 and June 2019 at our institution and excluded those with preoperative atrial fibrillation and those undergoing sex-specific surgery. We stratified the patients into four groups based on their sex and age: females younger than 50 years, females older than 50 years, males younger than 50 years, and males older than 50 years. The primary outcome was the incidence of POAF. Results: Of the 141,337 patients included in the study, 6414 (4.5%) were treated for POAF. The incidence of POAF was highest in males older than 50 years (7.4%), followed by females older than 50 years (4.6%), males younger than 50 years (2.1%), and females younger than 50 years (1.9%). After adjusting for potential confounding factors, the risk of POAF was significantly increased in all groups compared with females younger than 50 years, with an odds ratio (OR) of 2.43 (95% confidence interval [CI]: 2.17–2.73, p 0.001) for females older than 50 years, 1.19 (95% CI: 1.05–1.35, p = 0.01) for males younger than 50 years, and 4.39 (95% CI: 3.91–4.94, p 0.001) for males older than 50 years. The OR for POAF risk according to sex peaked between 60 and 70 years old and decreased gradually thereafter. Conclusions: Our study suggests that sex and age are important factors associated with the risk of POAF in non-cardiac surgery patients and that sex-specific and age-specific risk stratification and interventions might be needed to prevent and manage POAF in non-cardiac surgery patients. Further studies are needed to better understand the underlying mechanisms of sex and age differences in POAF and to develop more targeted and effective interventions to reduce the incidence of this common postoperative complication.