In Vietnam, vaccination has played a crucial role in the national strategy for the prevention and control of H5 highly pathogenic avian influenza (HPAI). This study aimed to evaluate antibody responses of immunologically naïve domestic ducks to H5N1 avian influenza vaccine currently used in the national mass vaccination program of Vietnam. Blood samples of 166 ducks reared on smallholder farms were individually collected at three sampling time points, namely, right before vaccination, 21 days after primary vaccination, and 21 days after booster vaccination. Vaccine-induced antibody titers of duck sera were measured by the hemagglutination inhibition assay. Temporal differences in mean antibody titers were analyzed using the generalized least-squares method. No sampled ducks showed anti-H5 seropositivity pre-vaccination. The geometric mean titer (GMT) of the vaccinated ducks was 5.30 after primary vaccination, with 80% of the vaccinated ducks showing seropositivity. This result indicates that the immunity of duck flocks met the targets of the national poultry H5N1 HPAI mass vaccination program. GMT and seropositive rates of the ducks were 6.48 and 96.3%, respectively, after booster vaccination, which were significantly higher than those after primary vaccination. Flock-level seroprotection rate significantly increased from 68% to 84.7%, whereas variability in GMT titers decreased from 34.87% to 26.3%. This study provided important information on humoral immune responses of ducks to the currently used H5N1 vaccine under field conditions. Our findings may help guide veterinary authorities in planning effective vaccine protocols for the prevention and control of H5N1 in the target poultry population.