Background There are wide differences in the uptake of skilled delivery services between urban and rural women in the northern region of Ghana. This study assessed the rural-urban differences in the prevalence of and factors associated with uptake of skilled delivery in the northern region of Ghana. Methods The study population comprised postpartum women who had delivered within the last three months prior to the study. The dataset was analyzed using the chi-square test and multivariable logistic regression. Results The odds of skilled birth attendance (SBA) adjusted for confounding variables in urban areas were higher compared with their rural counterparts (AOR = 1.59; CI: 1. 07–2.37; p=0.02). The determinants of skilled delivery were similar but of different levels and strength in rural and urban areas. The main drivers that explained the relatively high skilled delivery coverage in the urban areas were higher frequency of antenatal care (ANC) attendance, proximity (physical access) to health facility, and greater proportion of women attaining higher educational level of at least secondary school. Distance from health facility less than 4 km was the greatest independent contributor to the variance in skilled delivery in the urban areas, whereas frequency of ANC attendance was the greatest independent contributor in the rural areas. Conclusions This study identified underlying determinants accounting for rural-urban differences in skilled delivery, and covariate effect was more dominant than coefficient effect. Therefore, urban-rural differences in SBA outcomes were primarily due to differences in the levels of critical determinants rather than the nature of the determinants themselves. Therefore, improving skilled delivery outcomes in this study population and other similar settings will not require different policy frameworks and interventions in dealing with rural-urban disparities in SBA outcomes. However, context-specific tailored approaches and strategies including targeting mechanisms have to be designed differently to reduce the rural-urban differences.