Background The 2013-2016 Ebola Virus Disease (EVD) outbreak remains the largest on record, resulting in the highest mortality and widest geographic spread experienced in Africa. Ghana, like many other African nations, began screening travelers at all entry points into the country to enhance disease surveillance and response. This study aimed to assess the challenges of screening travelers for EVD at border entry in northern Ghana. Design and methods This was an observational study using epidemiological weekly reports (Oct 2014-Mar 2015) of travelers entering Ghana in the Upper East Region (UER) and qualitative interviews with 12 key informants (7 port health officers and 5 district directors of health) in the UER. We recorded the number of travelers screened, their country of origin, and the number of suspected EVD cases from paper-based weekly epidemiological reports at the border entry. We collected qualitative data using an interview guide with a particular focus on the core and support functions (e.g. detection, reporting, feedback, etc.) of the World Health Organization's Integrated Disease Surveillance and Response system. Quantitative data was analyzed based on travelers screened and disaggregated by the three most affected countries. We used inductive approach to analyze the qualitative data and produced themes on knowledge and challenges of EVD screening. Results A total of 41,633 travelers were screened, and only 1 was detained as a suspected case of EVD. This potential case was eventually ruled out via blood test. All but 52 of the screened travelers were from Ghana and its contiguous neighbors, Burkina Faso and Togo. The remaining 52 were from the four countries most affected by EVD (Guinea, Liberia, Sierra Leone, and Mali). Challenges to effective border screening included: inadequate personal protective equipment and supplies, insufficient space or isolation rooms and delays at the border crossings, and too few trained staff. Respondents also cited lack of capacity to confirm cases locally, lack of cooperation by some travelers, language barriers, and multiple entry points along porous borders. Nonetheless, no potential Ebola case identified through border screening was confirmed in Ghana. Conclusion Screening for Ebola remains sub-optimal at the entry points in northern Ghana due to several systemic and structural factors. Given the likelihood of future infectious disease outbreaks, additional attention and support are required if Ghana is to minimize the risk of travel-related spread of illness.