BACKGROUND: Malaria is a disease which still becomes a global health issue, including in Indonesia, because of its potential vector which can infect and spread causing a wide impact. Until currently, malaria still becomes a serious threat to people living in tropical and subtropical areas. Muara Enim Regency is a malaria-endemic regency with the second highest positive case in South Sumatra Province, with an API value in 2019 was 0.18/1000 population. AIM: The current research was performed to identify and change the spatial pattern of malaria cases, environmental variability (rainfall), population density using Moran index and local indicator spatial autocorrelation (LISA), and habitat in Muara Enim Regency. METHODS: This research employed a quantitative research design with an analytical survey research method and a case–control approach. This research method was designed using a geographic information systems approach. RESULTS: The results of the study showed that malaria cases in Muara Enim Regency in 2017 occurred in groups with a Moran index of 0.263, indicating a positive autocorrelation. Meanwhile, based on the LISA index, it was found that there were three districts categorized as high-high (HH) (quadrant 1), those are Lawang Kidul District, Muara Enim District, and Gunung Megang District, while in the low-high (LH) category (quadrant 2), there was Benakat District. In 2018, it also occurred in groups where the Moran index was 0.129, indicating a positive autocorrelation, while the LISA index found that there was one district categorized as HH (quadrant 1) which is Lawang Kidul District, and district categorized as LH (quadrant 2) was Gunung Megang District. In 2019, it happened randomly or spread with a Moran index of −0.022 indicating a negative autocorrelation, while based on the LISA index, it was found that there was one subdistrict categorized as HH category (quadrant 1) which is Lawang Kidul District and two districts categorized as LH (quadrant 2) which are Semende Darat Laut and Rambang Niru. CONCLUSION: There was a change in the results of Moran index from a positive autocorrelation in 2017, 2018, to a negative autocorrelation in 2019 with the results of the LISA index for malaria cases in 2017–2019 in one subdistrict, namely, Lawang Kidul District categorized as a HH category (quadrant 1).