In this work, a signal amplification strategy was designed by the fabrication of a highly sensitive and selective electrochemical sensor based on nickel-copper-zinc ferrite (NiCuZnFeO)/carboxymethyl cellulose (CMC)/graphene oxide nanosheets (GONs) composite modified glassy carbon electrode (GCE) for determination of omeprazole (OMP). The one-step synthesized NiCuZnFeO/CMC/GONs nanocomposite was characterized by scanning electron microscopy, energy-dispersive X-ray spectroscopy, transmission electron microscopy and X-ray diffraction techniques. Then, the NiCuZnFeO/CMC/GONs/GCE was applied to study the electrochemical behavior of the OMP. Electrochemical data show that the NiCuZnFeO/CMC/GONs/GCE exhibits superior electrocatalytic performance on the oxidation of OMP compared with bare GCE, GONs/GCE, CMC/GONs/GCE and MFeO/GCE (M = Cu, Ni and Zn including single, double and triple of metals) which can be attributed to the synergistic effects of the nanocomposite components, outstanding electrical properties of NiCuZnFeO and high conductivity of CMC/GONs as well as the further electron transport action of the nanocomposite. Under optimal conditions, the NiCuZnFeO/CMC/GONs/GCE offers a high performance toward the electrodetermination of OMP with the wide linear-range responses (0.24-5 and 5-75 μM), lower detection limit (0.22 ± 0.05 μM), high sensitivity (1.1543 μA μM cm), long-term signal stability and reproducibility (RSD = 2.54%). It should be noted that the NiCuZnFeO/CMC/GONs/GCE sensor could also be used for determination of OMP in drug and biological samples, indicating its feasibility for real analysis.