Undesired interfacial reaction between the high voltage spinel LiNi0.5Mn1.5O4 and commercial organic electrolyte is one of the most essential obstacles for the application of cathode material LiNi0.5Mn1.5O4 in lithium-ion batteries (LIBs). Here, to amend the high voltage cathode/electrolyte interface of LiNi0.5Mn1.5O4, we proposed a conformal nano-coating strategy by in-situ polymerization of poly(ethyl α-cyanoacrylate) (PECA) on its surface. The electrochemical measurement results demonstrated that the conformal PECA nano-coating film, acting as high voltage polymer electrolyte, transition metallic ions blocking layer, and buffer layer against electrolyte erosion and particle cracks, can successfully decrease polarization and enhance capacity retention during cycling of LiNi0.5Mn1.5O4. This work will inspire extensive and intensive research on the interface modification of LIBs.