In this research paper, a highly sensitive and selective molecular imprinted polymeric network (MIP) based electrochemical sensor was developed for the determination of histamine (HIS). The functional monomer (pyrrole) was electro-polymerized over the surface of AuNPs functionalized Fe-metal organic framework (Fe-BDC) and nitrogen-sulfur co-doped graphene quantum dots (N, S-GQDs). The MIP-Au@Fe-BDC/ N, S-GQDs /GCE exhibited an observable peak at −0.12 V, which corresponds to the anodic peak of Fe-BDC. This peak was increased and decreased by eluting and rebinding of HIS, respectively. This might be due to the binding constant between Fe-BDC and HIS is 3.5 × 10⁶ mol⁻¹ L. The electrochemical signal (Δi) was increased with the increase of HIS concentration in the range of 0.078–250 nM with a limit of detection (LOD, S/N = 3) of 0.026 nM. The combination of N, S-GQDs and Au@Fe-BDC improves the conductivity and the anchoring sites for binding the polymer film on the surface of the modified electrode. Factors affecting fabrication of MIP and HIS determination were optimized using standard orthogonal design using L25 (5⁶) matrix. The MIP-based electrochemical sensor offered outstanding sensitivity, selectivity, reproducibility, and stability. The proposed electrode was used to quantify HIS in human serum and canned tuna fish samples with recoveries % and relative standard of deviations % (RSDs %) in the range of 97.2–103 % and 1.8–3.8%, respectively. The as-synthesized MIP-based electrochemical sensor opens a new venue for the fabrication of MIP-based sensors and biosensors.