The prevalence and contributing factors of mental health issues among health workers in Vietnam during the early 2022 Omicron wave remain underexplored. This study investigated the prevalence and factors associated with anxiety and stress among health workers in a Vietnamese hospital during this period. A cross-sectional study, conducted from February 28 to April 14, 2022, at Hanoi Medical University Hospital, assessed anxiety and stress among 754 frontline health workers using the DASS-21 questionnaire via a Google survey. Logistic regression models were used to identify factors linked to anxiety and stress. Among healthcare workers, 22% experienced stress, and 33% anxiety. Multivariable logistic regression analysis revealed that direct contact with COVID-19 patients significantly increased the likelihood of experiencing stress (OR = 2.12, P < 0.01). Additionally, discrimination from relatives and friends was associated with higher odds of having anxiety (OR = 2.45, P < 0.001). Furthermore, a heavy workload significantly increased the odds of having anxiety (OR = 1.95, P < 0.001). Lastly, a lack of support from colleagues was linked to higher odds of experiencing stress (OR = 2.77, P < 0.05). The prevalence of mental health issues among Vietnamese health workers remained significant during the initial Omicron wave. Identified factors associated with these problems hold important policy implications for enhancing pandemic preparedness in Vietnam and worldwide.