Dengue fever (DF) outbreaks occur intermittently in Vietnam, and the most recent epidemic happened in 2017. However, attempts to measure the burden of DF in relation to the quality of life and the cost of treatment for patients during an epidemic period are constrained. This study explored the health-related quality of life (HRQOL) and the cost of illness among patients with dengue fever in Vietnam. A cross-sectional study was conducted in Bach Mai Hospital from September to November 2017. The EuroQol-5 dimensions-5 levels (EQ-5D-5L) was used to measure HRQOL. Cost-of illness was measured by collecting data about the direct medical cost, the non-medical cost, and the indirect cost. Among 225 patients, most of the participants experienced problems regarding mobility (62.3%), self-care (71.8%), usual activities (64.6%), and anxiety/depression (64.1%). The mean EQ-5D index was 0.66 (SD = 0.24). The median cost of illness for inpatient and outpatient groups were US $110.10 (IQR = US $4.40–1200.00) and US $36.10 (IQR = US $1.80–816.30), respectively. Indirect costs accounted for a major proportion in both groups. Lower-skilled workers and those with a higher severity of the disease had significantly lower HRQOL. Meanwhile, people who were inpatients, had comorbidities, had higher incomes, and who experienced a longer disease duration, had a higher cost of treatment. In conclusion, high costs and severe health deterioration, especially in psychological dimensions, were found in patients with DF in Vietnam. Strengthening primary health care services and communication campaigns are necessary to relieve the burden of diseases and could possibly contribute to effective DF control and prevention strategies.