Introduction Few economic evaluations have assessed the cost-effectiveness of screening type-2 diabetes mellitus (T2DM) in different healthcare settings. This study aims to evaluate the value for money of various T2DM screening strategies in Vietnam. Methods A decision analytical model was constructed to compare costs and quality-adjusted life years (QALYs) of T2DM screening in different health care settings, including (1) screening at commune health station (CHS) and (2) screening at district health center (DHC), with no screening as the current practice. We further explored the costs and QALYs of different initial screening ages and different screening intervals. Cost and utility data were obtained by primary data collection in Vietnam. Incremental cost-effectiveness ratios were calculated from societal and payer perspectives, while uncertainty analysis was performed to explore parameter uncertainties. Results Annual T2DM screening at either CHS or DHC was cost-effective in Vietnam, from both societal and payer perspectives. Annual screening at CHS was found as the best screening strategy in terms of value for money. From a societal perspective, annual screening at CHS from initial age of 40 years was associated with 0.40 QALYs gained while saving US$ 186.21. Meanwhile, one-off screening was not cost-effective when screening for people younger than 35 years old at both CHS and DHC. Conclusions T2DM screening should be included in the Vietnamese health benefits package, and annual screening at either CHS or DHC is recommended.