Malaria remains a serious public health challenge in Ghana including the Greater Accra Region. This study aimed to quantify the spatial, temporal and spatio-temporal patterns of malaria in the Greater Accra Region to inform targeted allocation of health resources. Malaria cases data from 2015 to 2019 were obtained from the Ghanaian District Health Information and Management System and aggregated at a district and monthly level. Spatial analysis was conducted using the Global Moran's I, Getis-Ord Gi*, and local indicators of spatial autocorrelation. Kulldorff's space-time scan statistics were used to investigate space-time clustering. A negative binomial regression was used to find correlations between climatic factors and sociodemographic characteristics and the incidence of malaria. A total of 1,105,370 malaria cases were reported between 2015 and 2019. Significant seasonal variation was observed, with June and July being the peak months of reported malaria cases. The hotspots districts were Kpone-Katamanso Municipal District, Ashaiman Municipal Districts, Tema Municipal District, and La-Nkwantanang-Madina Municipal District. While La-Nkwantanang-Madina Municipal District was high-high cluster. The Spatio-temporal clusters occurred between February 2015 and July 2017 in the districts of Ningo-Prampram, Shai-Osudoku, Ashaiman Municipal, and Kpone-Katamanso Municipal with a radius of 26.63 km and an relative risk of 4.66 (p < 0.001). Malaria cases were positively associated with monthly rainfall (adjusted odds ratio [AOR] = 1.01; 95% confidence interval [CI] = 1.005, 1.016) and the previous month's cases (AOR = 1.064; 95% CI 1.062, 1.065) and negatively correlated with minimum temperature (AOR = 0.86, 95% CI = 0.823, 0.899) and population density (AOR = 0.996, 95% CI = 0.994, 0.998). Malaria control and prevention should be strengthened in hotspot districts in the appropriate months to improve program effectiveness.