To determine the prevalence of postpartum depression (PPD) and postpartum stress (PPS) and identify associated risk factors among mothers of preterm and low birth weight (LBW) infants. We conducted a secondary analysis of data collected from 255 mothers with preterm and LBW infants admitted to the neonatal intensive care unit (NICU) at Korle-Bu Teaching Hospital, Accra, Ghana. A standardized interviewer-administered questionnaire collected data on maternal, pregnancy, birth, and infant characteristics. The questionnaire also included the Patient Health Questionnaire-9 (PHQ-9) and the Perceived Stress Scale-4 (PSS-4) to assess PPD and PPS, respectively. Simple and multivariable linear regression analyses were performed to identify factors associated with PPD and PPS. The prevalence of moderate to moderately severe PPD was 3.9%, and that of PPS was 43.5%. The multivariable linear regression analysis showed that an increased number of prenatal care visits (β-estimate = 0.26; 95% confidence interval [CI] 0.08-0.43; P < 0.01) was positively associated with higher scores on the PHQ-9, whereas gestational age at birth (β = -0.21; 95% CI -0.40 to -0.03; P = 0.02) was inversely associated with PHQ-9 scores. Moreover, a longer gestational period at the first prenatal care visit (β = 0.25; 95% CI 0.05-0.45; P = 0.01) and following the Islamic religion were associated with elevated scores on the PSS-4 (β = 0.95; 95% CI 0.11-1.80; P = 0.011). Our findings underscore the presence of moderate PPD levels and high PPS levels among mothers. Active screening, diagnosis, and treatment for mothers at risk of mental health disorders during the peripartum period could enhance coping mechanisms for mothers navigating the challenging NICU environment and transitioning to the home environment.