Abstract Background This paper investigates the impact of malaria preventive interventions in Ghana and the prospects of achieving programme goals using mathematical models based on regionally diverse climatic zones of the country. Methods Using data from the District Health Information Management System of the Ghana Health Service from 2008 to 2017, and historical intervention coverage levels, ordinary non-linear differential equations models were developed. These models incorporated transitions amongst various disease compartments for the three main ecological zones in Ghana. The Approximate Bayesian Computational sampling approach, with a distance based rejection criteria, was adopted for calibration. A leave-one-out approach was used to validate model parameters and the most sensitive parameters were evaluated using a multivariate regression analysis. The impact of insecticide-treated bed nets and their usage, and indoor residual spraying, as well as their protective efficacy on the incidence of malaria, was simulated at various levels of coverage and protective effectiveness in each ecological zone to investigate the prospects of achieving goals of the Ghana malaria control strategy for 2014–2020. Results Increasing the coverage levels of both long-lasting insecticide-treated bed nets and indoor residual spraying activities, without a corresponding increase in their recommended utilization, does not impact highly on averting predicted incidence of malaria. Improving proper usage of long-lasting insecticide-treated bed nets could lead to substantial reductions in the predicted incidence of malaria. Similar results were obtained with indoor residual spraying across all ecological zones of Ghana. Conclusions Projected goals set in the national strategic plan for malaria control 2014–2020, as well as World Health Organization targets for malaria pre-elimination by 2030, are only likely to be achieved if a substantial improvement in treated bed net usage is achieved, coupled with targeted deployment of indoor residual spraying with high community acceptability and efficacy.