Postpartum depression, a major depressive disorder, predisposes postnatal mothers to physical, social, and psychological malfunctioning. Purpose: The study aimed to identify the psychosocial determinants of postpartum depression and maternal well-being among mothers in the Accra metropolis. Materials and Method: A sample of 205 postnatal women between the ages of 15 -39 years and are 4 -12 weeks old postpartum was drawn from 37 Military Hospital, Accra. Employing a sequential explanatory approach, participants were administered the Depression, Anxiety and Stress Scale (DASS-21), Multidimensional Scale of Perceived Social Support (MSPSS), Marital Adjustment Test (MAT), and the Edinburgh Postnatal Depression Scale (EPDS). Findings: The study revealed that 14.1% of postnatal women in the Accra metropolis are at risk of developing PPD. A significant model emerged, [R2 = 0.488, F (7, 197) = 26.86, ρ < 0.05] and this was predicted by anxiety, stress and marital dissatisfaction among couples. On the other hand, results from Interpretive Phenomenological Analysis (IPA) of participants' in-depth information revealed inadequate social support and dissatisfaction in marriage account for mothers' at-risk behaviour of developing PPD; which impacts on maternal well-being. Conclusion: It is concluded that PPD is patent among postnatal women and psychosocial variables contribute a significant role in their experience of mental health problems following childbirth. This, in effect, requires attention from health professionals for holistic healthcare. The implications of these outcomes are discussed concerning mental healthcare delivery, the general public, and stakeholders in the health sector.