Ti6Al4V alloy has been widely used in dental applications, such as orthodontic mini-implants. However, it has been reported that fluoride ions could obviously accelerate the corrosion of implant materials and affect their performance. This work aimed to improve the F− erosion resistance of Ti6Al4V alloy through the strategy of both Cu addition and grain refinement. As contrasted with Ti6Al4V alloy, both the coarse- and ultrafine-grained Ti6Al4V-5Cu alloys effectively mitigated the acceleration of the fluoride ions to the anode process, because Cu substituents blocked the continuous damage of FO· doped in the passive film. Furthermore, grain refinement enhanced the protective ability of the passive film, more oxides and less adsorption amount of fluorides presented in the passive film of ultrafine-grained Ti6Al4V-5Cu alloy than those of coarse-grained Ti6Al4V-5Cu alloy. Under the combination of Cu alloying and grain refinement, the ultrafine-grained Ti6Al4V-5Cu alloy is greatly appropriate for the fabrication of orthodontic devices.