Purpose: Thalassemia is one of the most common monogenic diseases in southwestern China, especially among the Dai ethnic group. Here, we explore the feasibility of a next-generation sequencing (NGS) screening method specifically for the Dai people. Methods: Blood samples were obtained from Dai people for premarital screening. Double-blind, parallel hemoglobinopathy screening was conducted using both traditional hematological methods (red cell indexes and hemoglobin electrophoresis, then DNA sequencing) and an NGS approach. Results: Among 951 tested individuals, we found a thalassemia carrier rate of 49.5% (471/951) using the NGS screen, in contrast to 22.0% (209/951) found using traditional methods. Almost 74.8% (217/290) of alpha-thalassemia carriers and 30.5% (25/82) of composite alpha- and beta-thalassemia carriers were missed by traditional screens. The proportion of such alpha- and beta-thalassemia carriers among the Dai people is 8.6% (82/951). For beta-thalassemia carriers, the high ratio (66/99) of CD26 mutations may suggest a correlation between CD26 and the environmental adaption of the Dai people. Conclusions: Methodological comparisons demonstrate the superiority of NGS for both sensitivity and specificity, provide a comprehensive assessment of thalassemia screening strategies, and indicate that NGS is a competitive screening method, especially among populations with a high prevalence of disease.