Objective To investigate the diagnostic value of esophageal high-resolution manometry combined with salivary pepsin levels in laryngopharyngeal reflux disease (LPRD). Methods The patients with the chief complaint of “throat discomfort” for treatment at the Department of Otolaryngology, Head and Neck Surgery, the First People’s Hospital of Longquanyi District, Chengdu / West China Longquan Hospital Sichuan University between January and October 2022 was selected. According to the reflux findings score and refluxsymptomindex at admission, the enrolled patients were divided into LPRD group and non-LPRD group. The basic patient information, esophageal high resolution manometry, and salivary pepsin concentration of included patients were collected. Results A total of 112 patients were included. Among them, there were 68 cases (60.7%) in the LPRD group and 44 cases (39.3%) in the non-LPRD group. The LPRD group was significantly younger (P=0.007) , but the salivary pepsin concentration (P<0.001), upper esophageal sphincter (UES) resting pressure (P<0.001) and distal contractile integral (P=0.007) were all higher than the non-LPRD group. The results of multivariate logistic regression analysis showed that salivary pepsin concentration [odds ratio (OR)=1.077, 95%CI (1.035, 1.120), P<0.001] and UES resting pressure [OR=1.035, 95%CI (1.019, 1.052), P<0.001] were independent factors for the diagnosis of LPRD. The area under the working curve (0.971), specificity (0.99), and sensitivity (0.77) in the combined index were higher than those of saliva pepsin concentration and UES resting pressure. Conclusion Esophageal high resolution manometry and salivary pepsin are significant for the diagnosis of LPRD, and their combined application can improve the diagnostic value and also serve as an alternative method for the diagnosis of LPRD.