Background The impairment of gastrointestinal mucosa visibility during esophagogastroduodenoscopy (EGD), due to the presence of foam and bubbles, may lead to reduced quality in the EGD results. The combination of simethicone, a defoaming agent, along with N-acetylcysteine (NAC), which has mucolytic properties, has been proposed to improve the visibility of the mucosa. This study aimed to evaluate the effectiveness of pre-procedural administration of simethicone and N-acetylcysteine in improving mucosal visibility, procedure time and mucosal cleansing volume needed during EGD. Methods We conducted a comprehensive literature search from inception to November 23, 2023, in PubMed, CENTRAL, ProQuest, SAGE, and JSTOR. We included randomized clinical trials that investigated the effects of simethicone with or without NAC as premedication in EGD. For the quantitative analysis, standardized mean difference (SMD) was used to assess continuous outcomes and risk ratio for dichotomous outcomes. The Cochrane risk of bias 2 tool was used to evaluate the risk of bias. Results This meta-analysis comprised a total of 20 studies and found that simethicone with or without NAC improved mucosal visibility compared with control (SMD-1.27, 95% confidence interval [CI]-1.74 to-0.81, P<0.001). The combination of simethicone and NAC was significantly better than simethicone alone (SMD-0.68, 95%CI-1.08 to-0.28, P=0.001). Simethicone with or without NAC also shortened the procedure time compared to control (MD-1.40, 95%CI-2.67 to-0.12, P=0.03). The risk of bias was low with a moderate grade of certainty. Conclusion The administration of simethicone with or without NAC may improve EGD quality. © 2025 Hellenic Society of Gastroenterology.