Three different types of Zr-based MOFs derived from benzene dicarboxylic acid (BDC) and naphthalene dicarboxylic acid as organic linkers (ZrBDC, 2,6-ZrNDC, and 1,4-ZrNDC) were synthesized. They were characterized using X-ray diffraction analysis (XRD), X-ray photoelectron spectroscopy (XPS), Fourier-transform IR spectroscopy (FT-IR), and Transmission electron microscopy (TEM). Their hydrophilic/hydrophobic nature was investigated via contact angle measurements; ZrBDC MOF was hydrophilic and the other two (ZrNDC) MOFs were hydrophobic. The three MOFs were combined with MWCNTs as electrode modifiers for the determination of a hydrophobic analyte, flibanserin (FLB), as a proof-of-concept analyte. Under the optimized experimental conditions, a significant enhancement in the oxidation peak current of FLB was observed when utilizing 2,6-ZrNDC and 1,4-ZrNDC, being the highest when using 1,4-ZrNDC. Furthermore, a thorough investigation of the complex oxidation pathway of FLB was performed by carrying out simultaneous spectroelectrochemical measurements. Based on the obtained results, it was verified that the piperazine moiety of FLB is the primary site for electrochemical oxidation. The fabricated sensor based on 1,4-ZrNDC/MW/CPE showed an oxidation peak of FLB at 0.8 V vs Ag/AgCl. Moreover, it showed excellent linearity for the determination of FLB in the range 0.05 to 0.80 μmol L⁻¹ with a correlation coefficient (r) = 0.9973 and limit of detection of 3.0 nmol L⁻¹. The applicability of the developed approach was demonstrated by determination of FLB in pharmaceutical tablets and human urine samples with acceptable repeatability (% RSD values were below 1.9% and 2.1%, respectively) and reasonable recovery values (ranged between 97 and 103% for pharmaceutical tablets and between 96 and 102% for human urine samples). The outcomes of the suggested methodology can be utilized for the determination of other hydrophobic compounds of pharmaceutical or biological interest with the aim of achieving low detection limits of these compounds in various matrices.