Children with specific psychophysiological profiles may be more strongly affected by adverse environmental experiences. Guided by a biopsychosocial perspective, we examined whether infant respiratory sinus arrhythmia (RSA), an index of parasympathetic functioning, moderates the associations between paternal postpartum depression (PPD) symptoms and infants' observed empathy-related responses. Participants were 142 families with infants (51% female) assessed at two time points. At T1 (3 months of age), fathers reported their depressive symptoms. Infants' cardiac activity was recorded during rest and estimates of RSA were calculated. In addition, infants' empathy-related responses during a maternal distress simulation were observed and rated at T2 (12 months of age). Higher paternal PPD at T1 predicted higher infant affective (i.e., affective concern) and cognitive (i.e., inquiring behaviors) responses to maternal distress at T2. Infant RSA moderated this relationship for cognitive responses, with a significant positive association only for children with high or average RSA. These findings contribute to the understanding of the psychophysiological mechanisms that support empathy development.