Objective To characterize and determine risk factors for key dimensions of well-being at hospital discharge in families of neonates with acute symptomatic seizures. Study Design This prospective, observational cohort study enrolled 144 parent-infant dyads among neonates with acute symptomatic seizures from nine pediatric hospitals of the Neonatal Seizure Registry . One parent per family completed discharge surveys, which included measures of anxiety and depression, health related quality of life, and impact on the family. Multivariable regression analyses adjusted for site were constructed to examine parent and infant characteristics associated with well-being. Results At discharge, 54% of parents reported symptoms of anxiety and 32% reported symptoms of depression. Parents of infants with hypoxic-ischemic encephalopathy reported more depression and worse quality of life (QOL) than parents of infants with other seizure etiologies. Parental QOL was also lower with greater infant age at discharge. A higher level of maternal education was associated with greater impact on the family. All of these differences were medium to large effect sizes, ranging from 0.52 to 0.78. Conclusions Symptoms of anxiety and depression are common in parents of infants with neonatal seizures and several parent and infant characteristics are associated with poorer parental quality of life and family well-being. These findings are a call to action to improve mental health screening and services for parents of infants with neonatal seizures.