Abstract Background In this study, the factors that influence the choice of place of delivery among expectant mothers in both rural and urban settings in the northern part of Ghana were identified and compared using the conceptual framework provided by Thaddeus and Maine. Methods A mixed-method study was used to examine expectant mothers and their responses related to factors that affect their choice of place of delivery through a concurrent triangulation using health professional interviews and a detailed participant survey. The sample consisted of 552 expectant mothers between the ages of 15 and 49 years. Individual interviews were conducted with 8 health professionals. There was also a focus group discussion with randomly selected pregnant women and lactating mothers. Themes were generated through open coding of the interview data, while multiple regression was performed to identify the factors associated with choice of place of delivery. Results Major preference (60.1%) was for home delivery among rural dwellers compared to 20.7% for urban participants. Statistically significant variables affecting the choice of place of delivery among study participants were found to be educational background, the experience of previous deliveries, the attitude of hospital staff toward pregnant women during labor, and frequency of accessing antenatal care. Conclusion Majority of rural women prefer home delivery to facility delivery which is the opposite of the trend observed among urban women. The study’s implications may lead to positive change where stakeholders develop and implement policies to promote health facility delivery for expectant mothers in Ghana.