Introduction: Achieving high Mass Drug Administration (MDA) coverage and drug uptake are pivotal in the efforts to eradicate onchocerciasis. The present study investigated the extent and predictors of ivermectin MDA coverage and uptake from the individual and healthcare providers' perspectives. The extent of ivermectin distribution and uptake, and the predictors of distribution and uptake were investigated in endemic communities in the Ashanti Region of Ghana. Methods: A cross-sectional survey was conducted from August to October 2019 in communities within the Atwima Nwabiagya North District. A total of 2008 respondents were interviewed. Data was collected with REDCap mobile App which had an electronic version of the structured questionnaire. Descriptive data was presented in frequency tables, and bivariate and multivariate logistics regression analysis were performed to measure the associations between exposure variables and outcome variables which were received and uptake of MDA drugs. Results: A total of 1284 (63.9%) respondents did not receive ivermectin during the 2019 MDA programme and more than half of them were not aware of the drug distribution (53.3%). The most common reasons for not ingesting the drug were fear of side effects (47.7%) and not trusting the drug distributors (20.0%). Respondents in the age group 48–57 years (AOR = 1.37; 95%CI: 1.01–2.67), Persons in the high wealth index (AOR = 1.40; 95%CI: 1.11–1.77), Being aware of the MDA programme (AOR = 6.67: 95%CI: 4.76–9.35), MDA being beneficial (AOR = 2.12; 95%CI: 1.54–2.92) participating in previous MDA (AOR = 5.44; 95%CI: 4.25–6.98) and having stayed in the communities for 10 years and above significantly increased the odds of receiving MDA drugs. Previous uptake of MDA drugs (AOR = 10.58; 95%CI: 5.78–19.38) and perception of the MDA drug as beneficial (AOR = 5.25; 95%CI: 2.55–10.82) increased the likelihood of ingesting drugs when received. Conclusion: The main health system challenge was limited awareness creation regarding MDA. This seems to affect the optimal utilization of the ivermectin MDA intervention. MDA programmes against onchocerciasis eradication should be designed taking into account specific contextual factors to improve implementation outcomes.