Introduction: Malaria is a significant public health concern in Indonesia. Muara Enim Regency is one of the districts in South Sumatra with the most important number of indigenous malaria cases in the last three years (2018–2020). Therefore, this study aimed to identify determinants of indigenous malaria in the Muara Enim Regency. Methods: This study was designed as a case-control study. A stratified random sample in 2018, 2019, and 2020 was used at the Primary Health Centres (PHCs) areas of Tanjung Enim and Tanjung Agung. The sample included 49 cases and 49 controls. Indigenous malaria determinants were discovered using both bivariable and multivariable logistic regression models. Result: The multivariable logistic regression model results show that mosquito repellent reduces malaria risk by 71% (AOR = 0.29, 95% CI: 0.11–0.64). Besides, the presence of wire mesh on ventilation reduces the risk of malaria by 76% (AOR = 0.24, 95% CI: 0.10–0.57), and the distance from mosquito breeding sites near hundred meters and fewer increases the risk of malaria by 3.88 fold (AOR = 3.88; 95% CI: 1.67–8.97). Conclusions: Multivariable analysis revealed distance from mosquito breeding sites as a risk factor for malaria. Besides, the study shows that using insect repellent, wire netting in ventilation, eliminating mosquito breeding sites, mosquito repellent or protective clothing, and improving house conditions were protective factors for indigenous malaria. Therefore, preventive and promotional efforts are essential as the first step toward malaria elimination at the study site, including avoiding direct contact between residents and vectors near mosquito breeding sites.