α-Phase NaREF4 is the necessary intermediate to obtain β-phase NaREF4, which is good at upconversion luminescence. We herein report microreaction research on the generation of α-NaYF4:Yb,Er nanoparticles. Owing to the fast heating and cooling ability of a quartz microreactor, α-NaYF4:Yb,Er was successfully generated within a reaction time of <10 min. The results showed that it was difficult to complete the α-NaYF4:Yb,Er generation reaction in such a short reaction time by using the traditional synthetic route with a precursor solution containing NaF. However, as we changed the precursor to a solution containing amorphous NaREF4, the yield of α-NaYF4:Yb,Er increased to 95%. By focusing on applying the new precursor solution, we investigated the influence of the reaction temperature on the morphology of α-NaYF4:Yb,Er and exhibited the effects of size and crystallinity of α-NaYF4:Yb,Er on the generation of β-NaYF4:Yb,Er. Finally, an improved microreaction system with an in-line mixing of NH4REF4 and NaOA solutions was developed, whose products were successfully converted to uniform β-NaYF4:Yb,Er nanocrystals through the Ostwald-ripening process. The new reaction path and the reaction device further opened a door for the highly efficient synthesis of upconversion luminescent nanoparticles.