Background: Recent analyses have suggested an accelerated decline in child mortality in Ghana since 2000. This study examines the long-term child mortality trends in the country, relates them to changes in the key drivers of mortality decline, and assesses the feasibility of the country’s MDG 4 attainment. Methodology: Data from five Demographic and Health Surveys (DHS) between 1988 and 2008 and the Maternal Health Survey 2007 were used to generate two-year estimates of under-five mortality rates back to 1967. Lowess regression fitted past and future trends towards 2015. A modified Poisson approach was applied on the person-period data created from the DHS 2003 and 2008 to examine determinants of under-five mortality and their contributions to the change in mortality. A policy-modelling system assessed the feasibility of the country’s MDG 4 attainment. Findings: The under-five mortality rate has steadily declined over the past 40 years with acceleration since 2000, and is projected to reach between 45 and 69 per 1000 live births in 2015. Preceding birth interval (reference: 36+ months, relative risk [RR] increased as the interval shortened), bed net use (RR 0.71, 95% confidence interval [CI]: 0.52–0.95), maternal education (reference: secondary/higher, RR 1.71, 95% CI: 1.18–2.47 for primary), and maternal age at birth (reference: 17+ years, RR 2.13, 95% CI: 1.12–4.05) were primarily associated with under-five mortality. Increased bed-net use made a substantial contribution to the mortality decline. The scale-up of key interventions will allow the possibility of Ghana’s MDG 4 attainment. Conclusions: National and global efforts for scaling up key child survival interventions in Ghana are paying off these concerted efforts need to be sustained in order to achieve MDG 4.