This study aims to investigate the potential impact of the Plasmodium falciparum sporozoite (PfSPZ) vaccine and indoor residual spraying (IRS) on malaria transmission in Keerom, Papua. An optimal control model is introduced in this article for malaria transmission using a deterministic compartmental host–vector model. The model considers the potential impact of the new PfSPZ vaccine and IRS through a novel host–vector framework. Treatment failure is also accounted for in the model to provide a more realistic representation of the disease dynamics. Mathematical analysis regarding the existence and stability of equilibria is conducted rigorously, and the basic reproduction number is derived using the next-generation matrix approach. We found that the malaria-free equilibrium is always locally asymptotically stable when the basic reproduction number is less than 1. Conversely, using a center manifold approach, we showed that the malaria-endemic equilibrium is asymptotically stable when the basic reproduction number is greater than 1 but close to 1. Model parameter values are estimated using incidence data from Keerom, Papua, an area in Indonesia with one of the highest malaria incidences at the national scale. A global sensitivity analysis is conducted using Partial Rank Correlation Coefficients, which reveal the importance of vaccination and IRS strategies in reducing the basic reproduction number. Through cost-effectiveness analysis based on the optimal control simulation results, we find that although the IRS-only intervention appears to be the most cost-effective strategy, the combination of PfSPZ vaccination and IRS yields the greatest overall impact on reducing malaria transmission. In particular, the combined strategy produces the largest reduction in the number of infected individuals, while the IRS-only strategy gives the most favorable cost-effectiveness outcome. These results suggest that PfSPZ vaccination and IRS can provide important benefits for malaria control in high-endemic areas such as Keerom, Papua.