The simultaneous use of two passive methods (twisted tape and a nanofluid) in a heat transfer system will increase the average Nusselt number (Nu) of the system. However, the presence of inserts and nanoparticles inside the tube will create higher pressure drop (ΔP) in the system, which can eventually affect the overall enhancement ratio (η), especially at higher Reynolds numbers (Re). Several modifications of twisted tapes have been made to reduce ΔP, but most showed a decreasing trend of η as Re increased. The objective of this study is to design a new geometry of twisted tape that yields a larger value of Nu and a smaller value of ΔP, which can result in a larger value of η especially at higher Re. A simulation and experimental analysis are conducted in which Re ranges from 4000–16,000 with two types of nanofluids (SiC/Water and Al2O3/Water) at various values of the volume fraction, (φ) (1–3%). ANSYS FLUENT software with the RNG k-ɛ turbulent model is adopted for the simulation analysis. Three types of twisted tape are used in the analysis: classic twisted tape with a pitch ratio of 2 (TT PR2), constant-increasing-pitch-ratio twisted tape (TT IPR) and constant-decreasing-pitch-ratio twisted tape (TT DPR). The use of TT IPR generates a stronger swirling flow at the inlet of the tube and smaller ∆P, especially near the outlet region. The highest value of η is obtained for 3% SiC/Water nanofluid that is flowing through a smooth circular tube with TT IPR inserts at Re of 10,000.