Background: Postoperative atrial fibrillation (AF) has a complex etiology, and beta-blockers are commonly recommended for its pharmacological prevention. This study aims to assess the impact of beta-blocker therapy on postoperative AF occurrence in patients undergoing aortic valve replacement, mitral valve replacement, surgical revascularization of the myocardium, or a combination of these procedures. Methods: The study encompassed 472 patients who received aortic valve replacement, mitral valve replacement, surgical revascularization, or their combination. We evaluated the efficacy of preoperative and one-month postoperative beta-blocker administration in preventing postoperative AF, and the associated risk factors involved in the development of postoperative AF. Results: Of the total patient population, 36% experienced postoperative AF. Our study demonstrated a significant reduction in postoperative AF incidence among patients receiving beta-blocker treatment (all p-values 0.05). Additionally, one-month post-surgery, beta-blocker treatment exerted a protective effect by maintaining the sinus rhythm (p = 0.0001). Regarding the risk factors involved in the development of postoperative AF, both age and left atrium (LA) sizeassessed pre-and postoperatively—were positively correlated with the occurrence of postoperative AF (p = 0.006). No relationship was found between leukocyte counts and AF incidence. Notably, C-reactive protein (CRP) levels were significantly elevated on the fifth postoperative day in patients with AF (p 0.007). The duration of ischemia was significantly longer in patients with AF (p = 0.009). Conclusions: This study establishes the efficacy of perioperative beta-blocker treatment in mitigating postoperative AF. One month post-surgery, most patients under beta-blocker therapy maintained sinus rhythm, suggesting a potential long-term protective effect of beta-blockers against late-onset AF.