(1) Background: the prevalence of postnatal depression (PND) reaches up to 20%. PND could be based on the interaction between a psychological vulnerability and chronic stress that pregnancy would activate. Vulnerability factors reflect a psychological profile mirroring mindfulness-trait (MT). A high level of MT is associated with an efficient regulation of both physiological and psychological stress, especially negative moods. Interestingly, mindfulness level can be improved by program based on mindfulness meditation. We hypothesize that MT is a protective factor for PND. We also postulate that negative moods increase during the pregnancy for women who develop a PND after delivery (2) Methods: we conducted a multicentric prospective longitudinal study including 85 women during their first trimester of their pregnancy and 72 from the childbirth to the baby’s first birthday”. At the inclusion, presence and acceptance of MT and various variables of personality and of psychological functioning were assessed. Mood evolution was monitored each month during the pregnancy and a delivery trauma risk was evaluated after delivery. PND detection was carried out at 48 h, 2, 6 and 12 months after the delivery with the Edinburgh Postnatal Depression Scale with a screening cut-off >11. (3) Results: high-acceptance MT is a protective factor for PND (OR: 0.79). Women without PND displayed less negative mood during pregnancy (p < 0.05 for Anxiety, Confusion and Anger). (4) Conclusions: these results suggest the value of deploying programs to enhance the level of mindfulness, especially in its acceptance dimension, before, during and after pregnancy, to reduce the risk of PND. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.< Réduire