People living in coastal areas are frequently affected by natural disasters, such as floods and storms. This study aimed to assess the quality of life (QoL) of people living in disadvantaged coastal communes (subdivision of Vietnam) and identify their associated factors by using the World Health Organization’s quality of life instrument (WHOQOL-BREF). To achieve this, a cross-sectional descriptive study was conducted on 595 individuals aged 18 years and above living in the coastal communes in Thua Thien Hue province, Vietnam, from October 2022 to February 2023. The results showed that the mean overall QoL (mean ± SD) was 61.1 ± 10.8. Among the four domains of QoL, the physical health (57.2 ± 12.3) domain had a lower score than the psychological health (61.9 ± 13.0), social relations (63.4 ± 13.4), and environment (61.9 ± 13.3) domains. The QoL score of the domains for participants affected by flooding was significantly lower than that of those not affected, except for social relations. Multivariable logistic regression showed that subjects with not good QoL had the educational background with no formal education (Odds ratio (OR) = 2.63, 95% CI 1.19–5.83), fairly poor/poor households (OR = 2.75, 95% CI 1.48–5.12), suffered Musculoskeletal diseases (OR = 1.61, 95% CI 1.02–2.56), unsatisfaction with health status (OR = 5.27, 95% CI 2.44–11.37), family conflicts (OR = 4.51, 95%CI 2.10–9.69), and low levels of social support (OR = 2.62; 95% CI 1.14–6.02). The analysis also revealed that workers (OR = 0.17, 95% CI 0.04–0.66) had a better QoL than farmer-fisherman. QoL in disadvantaged coastal communes was low, with the lowest scores in the physical health domain. Based on the socioeconomic factors associated with not good QoL identified here, it is recommended that local authorities take more appropriate and practical measures to increase support, including measures for all aspects of physical health, psychological health, social relations, and the living environment, especially for people affected by floods.