The prevalence of highly pathogenic avian influenza (HPAI) has become substantial obstacles for the poultry industry and international trade with potential threat to human health. We developed a data-driven transmission model for quantitatively assessing the risk of HPAI spread in a henhouse under the China national mandatory vaccination plan for prevention and control of HPAI in the poultry industry. With data from farm investigations and literature reviews, we calibrated our model to estimate some key model parameters. We employed the Latin Hypercubic Sampling (LHS) technique for multiple sampling during simulations and subsequently conducted statistical analysis to enhance the accuracy and reliability of our results. We found that within a designated single henhouse, within a designated single henhouse, regardless of whether the initial virus level is 5 or 500 times the minimum viral load required to trigger highly fatal avian influenza, when the virus transmission capacity is low (the basic reproductive number R0 ∈ (2, 3)) implementing mandatory vaccination measures according to the policy-stipulated timings will keep the average overall mortality rate of chickens with maternal antibodies within the range of 0.08%-0.42%. However, if the virus transmission capacity doubles, the loss of chickens will increase by 3-5 times, but it will still be significantly lower than the normal mortality rate (5%). Therefore, to optimize post-vaccination management and control, we recommend monitoring flock antibodies regularly, evaluating vaccine effectiveness promptly, strengthening pathogen surveillance, and upgrading farm biosecurity level. These measures are essential for safeguarding flock immunity, facilitating early virus detection, and mitigating the risk of HPAI transmission.