This study explored the influence of both assisted reproductive technology (ART) and reduced quality of life (QoL) during pregnancy on postpartum blues (PPB). Sixty-three sub-fertile patients who conceived through ART and 72 women who naturally conceived were enrolled in this prospective study. At 22nd and 32nd gestational weeks, women completed the Edinburgh Postnatal Depression Scale (EPDS) and the Short-Form 36 (SF-36), to investigate depressive symptoms and QoL, respectively; EPDS was again used at 15 days after birth to assess PPB. At both time points, higher EPDS scores and lower mental well-being scores (SF-36) significantly predicted PPB. The number of previous ART cycles emerged as the strongest predictor, whereas no significant effect was observed for the conceiving method. The results suggest the usefulness of assessing QoL during pregnancy and considering previous ART failures in preventing PPB.