Introduction: In spite of the national target of achieving at least an 80% skilled delivery, skilled health providers attended to just 56.2% of deliveries in 2016 according to the Ghana Health Service annual report. The highest proportion of ANC registrants in the Akuapem South District in the Eastern Region of Ghana who sought skilled attendance at birth for the past 3 years has been about 36% as recorded in 2017. The fundamental factors responsible for this low skilled delivery in the district are poorly understood. The aim of this study, however, was to explore the factors that contribute to the uptake of skilled delivery in the Akuapem South District. Methodology: This cross-sectional study involved 371 women in the reproductive ages (15 - 49 years) who had delivered within the last 12 months preceding January 2019, and have been residents in the research communities during the period of pregnancy. A convenient sampling technique was used to select all 371 respondents from 15 communities. Structured questionnaires were used for the interviews by trained staff. Results: The prevalence of skilled delivery among respondents in this district as revealed by this study was 65.77% despite the 97.04% reported ANC attendance for at least once. Significant influencers of the uptake of skilled delivery were; maternal age, mother and partner’s educational level, partner’s occupation, the attitude of health staff/midwives, distance to the nearest health facility, transportation fare, and availability of medical equipment in the nearest health facility. Conclusion: Even though the overall ANC attendance was high, including women who made more than three visits, uptake of supervised delivery is a major challenge. There is, therefore, the need for the Akuapem South District Health Directorate to fully strengthen the adopted WHO’s goal that focuses on ANC at the individual facility levels.