Postpartum depression (PPD) is a severe mental illness affecting 10–15% of mothers. Emerging evidence indicates that negative neurocognitive bias in response to infant distress during pregnancy marks an increased risk of PPD. This proof-of-concept study aimed to investigate the association between negatively biased neurocognitive processing of infant distress during pregnancy and subsequent PPD and to explore the feasibility of an online risk screening tool. In the second or third trimester of pregnancy, 87 participants underwent two online tests of reactivity to and evaluation of infant distress and completed questionnaires regarding psychosocial risk factors. After birth, participants rated their depressive symptoms online and underwent a diagnostic telephone interview concerning PPD. Irrespective of depressive symptoms during pregnancy, negative reactivity to and evaluation of infant distress predicted PPD (reactivity: Exp(B)=1.33, p = 0.04) and depressive symptoms after birth (reactivity: B = 0.04, p = 0.048; evaluation: B = 0.10, p = 0.04). The negative reactivity toward infant distress showed high sensitivity and moderate specificity (89% and 77%, respectively), while the evaluation of infant distressed cries showed lower sensitivity and specificity (67% and 66%, respectively). The relatively small sample size prevented the inclusion of additional risk variables in the regression models. The replication of an association between negative neurocognitive bias during pregnancy with PPD risk is noteworthy and has clinical implications in terms of early prevention. However, the low response rate indicates that this tool is not feasible in its current form. Future larger-scale studies are needed to further investigate candidate risk factors in a brief online screening tool.