This cohort study quantifies the long-term impact of HPAI H5N1 on cumulative milk yield and milk-yield trajectories during the affected lactation, and carryover effects in the subsequent lactation; and evaluates the relationship between antibody response and affected status under field conditions. A cohort of 1,845 lactating Holstein cows from a commercial dairy herd affected by HPAI H5N1 was monitored across current and subsequent lactations. HPAI affected status was defined as ≥ 30% decline in daily milk yield relative to a 7-d baseline. Milk yield trajectories were analyzed using generalized additive mixed models with spline-based smooth terms for time, including a random intercept for cow and fixed effects for parity, stage of lactation, and HPAI affected status. Associations between antibody response and affected status were evaluated using multivariable logistic and linear regression models, adjusted for parity and stage of lactation. Affected animals (n = 772) had an average cumulative milk loss of 9.6% (1,109 kg) per 305 d, representing an average loss of $569 per affected cow. Higher losses occurred in multiparous (?12.4%) than primiparous cows (?3.9%). Retention into the subsequent lactation was similar between affected and unaffected cows (69.8% vs. 69.2%, respectively), and no evidence of carryover effects was detected. Based on post-outbreak serologic testing (n = 121), multiparous cows had higher odds of testing ELISA-positive for antibodies to HPAI than primiparous cows (OR = 2.48, 95% CI: 1.07–6.28). The adjusted predicted proportions of cows classified as affected based on the milk-yield decline criterion during the HPAI outbreak were 63.2% among ELISA-positive cows, 42.1% among ELISA-suspect cows, and 33.2% among ELISA-negative cows. ELISA-positive cows had higher odds of experiencing severe milk-yield decline than ELISA-negative cows (OR = 3.45, 95% CI:1.44–8.69). Cows with stronger antibody response had higher odds of being classified as affected based on the milk-yield decline (OR = 0.51 per 0.05 S/N increase; 95% CI:0.35–0.75). Overall, cows affected during the HPAI outbreak had substantial milk-yield and economic losses during the affected lactation. Limited recovery was most evident among multiparous cows and among cows affected in early lactation, regardless of parity. No evidence of carryover effects was observed in the subsequent lactation. Stronger post-outbreak antibody responses were associated with affected status during the outbreak, defined by milk-yield decline as a clinically relevant sign.