Background: This study investigated malaria transmission under various contrasting settings in the Central Region, a malaria endemic region in Ghana. Methods: This cross-sectional study was carried out in five randomly selected districts in the Central Region of Ghana. Three of the districts were forested, while the rest was coastal. Study participants were selected to coincide with either the regular rainy or dry season. From each study site, hospital attendees were randomly selected with prior consent. Consciously, study participants were selected in both rainy (September and October, 2020) and dry (November and December, 2020) seasons. Clinical data for each patient was checked for clinical malaria suspicion and microscopic confirmation of malaria. Using SPSS Version 24 (Chicago, IL, USA), bivariate analysis was done to determine the association of independent variables (ecological and seasonal variations) with malaria status. When the overall analysis did not yield significant association, further statistical analysis was performed after stratification of variables (into age and gender) to determine whether any or both of them would significantly associate with the dependent variable. Results: Of the 3993 study participants, 62.5% were suspected of malaria whereas 38.2% were confirmed to have clinical falciparum malaria. Data analysis revealed that in both rainy and dry seasons, malaria cases were significantly higher in forested districts ) than coastal districts (x2 = 217.9 vs x2 = 50.9; p < 0.001). Taken together, the risk of malaria was significantly higher in the dry season (COR = 1.471, p < 0.001) and lower in coastal zones (COR = 0.826, p = 0.007). There was significant reduced risk of participants aged over 39 years of malaria (COR=0.657, p < 0.001). Whereas, in general patients between 10 and 19 years were insignificantly less likely to have malaria (COR = 0.911, p = 0.518) compared to participants aged less than < 10 years, the reverse was observed in coastal districts where patients less than 10 years of age in coastal districts were less likely to have malaria (COR=2.440, p = 0.003). In general, gender did not associate with malaria, but when stratified by study district, the risk of female gender to malaria was significantly higher in Agona Swedru (COR = 5.605, p < 0.001), Assin central (COR = 2.172, p < 0.001), Awutu Senya (COR = 2.410, p < 0.001) and Cape Coast (COR = 3.939, p < 0.001) compared to Abura-Asebu-Kwamankese. Conclusion: This study demonstrated that the predictors of malaria differ from one endemic area to another. Therefore, malaria control interventions such as distribution of long-lasting insecticide treated bed nets, residual spraying with insecticide and mass distribution of antimalaria prophylaxis must be intensified in forested districts in all seasons with particular attention on females. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. CC_BY_NC_ND_4.0