Objective: To identify risk factors of postpartum depression (PPD) and explore lived experiences to understand the social, psychological, and emotional mechanisms explaining being at higher likelihood of PPD. Design: Mixed method, cross-sectional study design. Setting: Three hospitals in Ho, Ghana. Population: 399 postpartum women aged 18 years and above. Methods: We used multivariable binomial generalized linear models to identify factors independently associated with PPD. We used thematic analysis to identify themes that highlight pathways through which these risk factors influence PPD. Main outcome measure: Screened positive for PPD. Results: Overall, 117 (29.3%) screened positive for PPD. Being unmarried (adjusted prevalence ratio, aPR, 1.33, 95% CI 1.02-1.72), lack of partner support (aPR 1.60, 95% CI 1.21-2.12), history of depressive or psychiatric disorders (aPR 2.44, 95% CI 1.84-3.25), unplanned pregnancy (aPR 1.63, 95% CI 1.18-2.25), low self-esteem (aPR 2.38, 95% CI 1.79-3.16), and low birthweight (aPR 1.87, 95% CI 1.33-2.65) were independently associated with PPD. The thematic analysis revealed four key themes: 1) social isolation and limited support, 2) emotional stress and vulnerability, 3) self-image and identity challenges, and 4) resilience resources. Conclusion: Our findings stress the urgent need for targeted interventions that address individual and structural factors to promote early screening, accessible mental health care, and programs that encourage partner involvement, and support unmarried mothers to enhance maternal well-being.