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Background: Onchocerciasis, also known as "river blindness", is caused by the bite of infected female blackflies (genus Simuliidae) that transmit the parasite Onchocerca volvulus. A high onchocerciasis microfarial load increases the risk to develop epilepsy in children between the ages of 3 and 18 years. In resource-limited settings in Africa where onchocerciasis has been poorly controlled, high numbers of onchocerciasis-associated epilepsy (OAE) are reported. We use mathematical modeling to predict the impact of onchocerciasis control strategies on the incidence and prevalence of OAE. Methodology: We developed an OAE model within the well-established mathematical modelling framework ONCHOSIM. Using Latin-Hypercube Sampling (LHS), and grid search technique, we quantified transmission and disease parameters using OAE data from Maridi County, an onchocerciasis endemic area, in southern Republic of South Sudan. Using ONCHOSIM, we predicted the impact of ivermectin mass drug administration (MDA) and vector control on the epidemiology of OAE in Maridi. Principal findings: The model estimated an OAE prevalence of 4.1% in Maridi County, close to the 3.7% OAE prevalence reported in field studies. The OAE incidence is expected to rapidly decrease by >50% within the first five years of implementing annual MDA with good coverage (≥70%). With vector control at a high efficacy level (around 80% reduction of blackfly biting rates) as the sole strategy, the reduction is slower, requiring about 10 years to halve the OAE incidence. Increasing the efficacy levels of vector control, and implementing vector control simultaneously with MDA, yielded better results in preventing new cases of OAE. Conclusions/Significances: Our modeling study demonstrates that intensifying onchocerciasis eradication efforts could substantially reduce OAE incidence and prevalence in endemic foci. Our model may be useful for optimizing OAE control strategies. Author summary: Onchocerciasis is a parasitic disease caused by the filarial worm Onchocerca volvulus, which is transmitted by Simuliidae black flies. This disease is most common in Africa and South America. Onchocerca volvulus is thought to infect approximately 35 million Africans these days. Adult female worms infect people and form subcutaneous nodules, releasing thousands of microfilariae per day, causing itching, dermatitis, blindness, and epilepsy. Despite the fact that the association between onchocerciasis and epilepsy was already mentioned in a study from Mexico in 1938, this association was only reported around 1991 in Africa in the Mbam valley in Cameroon. Onchocerciasis-associated epilepsy (OAE) is characterised by seizures that start between the ages of 3 and 18 years in previously healthy children with a high degree of O. volvulus infection. Raising awareness about OAE will increase adherence to community-directed treatment with ivermectin (CDTI), particularly in high-prevalence areas, while also motivating funders and stakeholders to keep fighting onchocerciasis. Here, we create an OAE model within the framework of ONCHOSIM that is parametrized using South Sudan data and investigate how different control measures such as CDTI and vector control might help reduce OAE in the future. [ABSTRACT FROM AUTHOR]