In this paper, while numerically simulating the Al2O3–water nanofluid flow in flat tubes fitted with twisted tapes, the effects of three different Heat Transfer Enhancement (HTE) methods are also separately evaluated and compared. These three HTE mechanisms include the use of nanofluid instead of the base fluid, use of flat tubes instead of circular tubes and the use of twisted tapes inside the tubes. The obtained results indicate that although all the three mentioned mechanisms improve the heat transfer within the tubes, the HTE due to the use of twisted tapes is greater than that caused by the other two mechanisms. After discovering that the simultaneous use of the three mentioned mechanisms can considerably increase the amount of heat transfer, three different arrangements of the twisted tapes in the nanofluid-containing flat tubes are also evaluated and compared. These three arrangements include the use of one twisted tape, use of two twisted tapes in the same direction and the use of two twisted tapes in different directions. The obtained results indicate that the use of two twisted tapes in different directions leads to the highest amounts of heat transfer and pressure drop in flat tubes.