ABSTRACTFlaviviruses such as dengue virus (DENV), Zika virus (ZIKV), and Japanese encephalitis virus (JEV) pose a major health burden in Vietnam, where overlapping clinical features and serological cross‐reactivity complicate accurate diagnosis and outbreak control. This study aimed to investigate circulating DENV serotypes and assess serological cross‐reactivity with other flaviviruses during the 2016 dengue outbreak in central Vietnam. Aretrospective study was conducted on 146 hospitalized dengue patients during the 2016 outbreak in Binh Dinh province. Laboratory diagnosis included NS1antigen testing, ELISA (IgM/IgG), and real‐time RT‐PCR for DENV serotyping. IgM and IgG cross‐reactivity with five flaviviruses, including DENV, ZIKV, JEV, West Nile virus (WNV), and tick‐borne encephalitis virus (TBEV), and onealphavirus, chikungunya virus (CHIKV), was evaluated using ELISA. DENV‐1 positive samples were further analysed by sequencing the capsid‐premembrane (CprM) gene. DENV‐1 was the predominant serotype (86%), with all sequenced strains clustering within genotype I. Secondary infections were more frequent (64%) than primary infections (36%) and were associated with a significantly higher median age (p = 0.003) and elevated hs‐CRP levels (p = 0.029). Strong IgG cross‐reactivity was observed among flaviviruses, particularly DENV, JEV, WNV, and TBEV (r > 0.85), while ZIKV and CHIKV showed low seropositivity. Incontrast, IgM responses demonstrated greater virus specificity. Ten PCR‐negative cases showed broad serological reactivity, suggesting possible misdiagnosis or late‐stage infection. Our findings reveal that DENV‐1 genotype I was the predominant serotype during the 2016 outbreak in central Vietnam. Extensive IgG cross‐reactivity among flaviviruses hinders serological diagnosis, highlighting the need for integrated molecular surveillance to ensure accurate outbreak response.