Elevated resistance to pyrethroids has led to the introduction of novel insecticides including neonicotinoids. However, the efficacy of these new control products could be impacted by cross-resistance mechanisms from metabolic resistance to pyrethroids. In this study, after evaluating the resistance to clothianidin and mixture of clothianidin+deltamethrin in the lab using CDC bottle assays, the efficacy of the new IRS formulation Fludora® Fusion IRS was tested in the experimental huts against wild free-flying pyrethroid-resistant Anopheles funestus in Elende and field An. gambiae from Nkolondom, Cameroon. Additionally, cone tests were performed on the wall of treated huts each month to evaluate the residual efficacy of the sprayed products. Furthermore, the L1014F-kdr target site mutation and the L119F-GSTe2 mediated metabolic resistance to pyrethroids were genotyped on a subset of mosquitoes from the EHT to assess the potential cross-resistance. All Anopheles species tested were fully susceptible to clothianidin and clothianidin+deltamethrin mixture in CDC bottle assay while resistance was noted to deltamethrin. Accordingly, Fludora® Fusion and clothianidin induced significantly higher mortality rates in EHT than deltamethrin with mortality rates of 62.83%, 64.42% and 42.42% against free flying An. funestus from Elende. However, lower mortality rates were recorded against An. gambiae from Nkolondom (mortality rates 50%, 45.56% and 26.68%). In-situ cone test on the wall showed a high residual efficacy of Fludora® Fusion and clothianidin on the susceptible strain KISUMU (>12 months) and moderately on the highly pyrethroid-resistant An. gambiae strain from Nkolondom (6 months). Interestingly, no association was observed between the L119F-GSTe2 mutation and the ability of mosquitoes to survive exposure to Fludora® Fusion, whereas a trend was observed with the L1014F-kdr mutation. This study highlights that Fludora® Fusion, has good potential of controlling pyrethroid-resistance mosquitoes with prolonged residual efficacy. This could be therefore an appropriate tool for vector control in several malaria endemic regions.