Currently, deep eutectic solvents (DESs), as an exclusive class of ionic liquid analogs, are extensively employed in various fields. Herein, vanadium phosphorus oxide (VPO) catalysts assisted by copper-based deep eutectic solvent (Cu-DES) as an electronic promoter and structure directing agent were ingeniously synthesized and exploited in the selective oxidation of n-butane to maleic anhydride (MA). The DES is efficient, cost effective and highly green compared to conventionally use metal inorganic modifiers. Cu-DES was prepared from a eutectic mixture of an organic salt (ChCl) and a metal salt hydrate/metal salt of cupric (Cu(NO3)2.3H2O, CuCl2) and cuprous (CuCl) salt with a molar ratio of 1:1–1:3, which notably improved the catalytic performance compared to that of an unpromoted VPO catalyst. The MA selectivity and n-butane conversion of Cu–DES–VPO increased significantly, while the COx (CO and CO2) selectivity decreased. FTIR, DSC, XRD, SEM, EDS, TEM, Raman, TGA, XPS, and NH3-TPD characterization techniques were utilized to fully analyze the DES, precursor and catalyst to explore MA selectivity. This work shifts the significant increase of 13% n-butane conversion, 11% MA selectivity and 16% MA mass yield, which greatly influences low carbon alkane utilization. Importantly, the CO: CO2 ratio is reduced from 2.02 to 1.62, which is more beneficial for chemical plants as well as green environments.