Objective To investigate the clinical efficacy and safety of Trimebutine Maleate combined with Esomeprazole in the treatment of gastroesophageal reflux disease (GERD). Methods A total of 75 patients with gastroesophageal reflux disease admitted to the Department of Gastroenterology and Nephrology of the Second People′s Hospital of Guangshui City from August 2019 to August 2020 were selected as the research subjects, and divided into observation group (n=38) and control group (n=37) by random touch ball method. The control group was treated with Esomeprazole,and the observation group was treated with Esomeprazole and Trammebutine Maleate. The clinical efficacy of the two groups was compared. The motor function indexes of distal esophageal smooth muscle (distal contraction integral [DCI],perperistaltic contraction ratio, lower esophageal sphincter relaxation ratio [LESRR] and low esophageal sphincter pressure [LESP]), gastroesophageal reflux disease health-related quality of life scale (GERD-HRQL) and gastroesophageal reflux disease quality scale (GerdQ) scores were compared between the two groups before and after treatment. Results The total effective rate of the observation group after treatment was higher than that of the control group, and the LESP,perperistaltic contraction ratio, LESRR and DCI of the observation group after treatment were all lower than those of the control group, with statistically significant differences (P＜0.05). The GERD-HRQL scores of each dimension of the observation group after treatment were lower than those of the control group, and the GerdQ score of the observation group after treatment was lower than that of the control group, with statistically significant differences (P＜0.05). There was no adverse reaction in the two groups during treatment. Conclusion Trimebutine Maleate combined with Esomeprazole can improve the therapeutic effect of patients with gastroesophageal reflux disease, improve the smooth muscle movement function of patients with lower esophagus, and improve the symptoms and quality of life of patients,which is safe and reliable.