Background This study was dedicated to developing the first facile and sustainable square wave voltammetric (SWV) method for simultaneous analysis of a combination of quercetin (QR) and paracetamol (PC) in biological specimens. A pioneering sensor, symbolized as SP@Zr-Adipate-MOF/CPE, was fabricated for the first time. Silver-protein (SP)-functionalized Zirconium (Zr)-Adipate-Metal organic framework (MOF) nanocomposites were prepared by one-pot synthesis procedure and encapsulated on a carbon paste (CPE). The interaction of SP@Zr-Adipate-MOF nanocomposite was explored by spectroscopic, and X-ray diffractometry studies. The SP@Zr-Adipate-MOF/CPE sensor was entirely characterized using cyclic voltammetry, scanning electron microscopy, and electron impedance spectroscopy measurements. Results The sensor's stability and reproducibility were evaluated and confirmed. This sensor demonstrated uniform morphology, large electroactive surface area (13.48 mm2), low charge transfer resistance (673.47 Ω), and outstanding electrocatalytic efficacy toward QR-PC combined therapy. The analytical SWV procedure employing the newly constructed sensor (SP@Zr-Adipate-MOF/CPE) was developed, optimized, and validated following the guidelines of analytical method validation. The target analytes were electrooxidized in a phosphate buffer solution of pH 6.5 within linearity ranges of 0.01–0.1 and 0.3–1.0 μM for QR and 0.1–1.0 and 3.0–10.0 μM for PC. Acceptable values of correlation and determination coefficients (0.9945–0.9989 and 0.9890–0.9978, correspondingly) were realized, justifying the linearity of the established SWV approach. The calculated limits of detection were 0.197 and 3.24 nM for QR and PC, respectively. The accuracy and repeatability of SWV procedure were proven as the recovery percentages ranged from 99.17 % to 101.08 %, and the relative standard deviation (RSD) values didn't exceed 2.11 %. The proposed SWV approach was effectively applied to concurrent estimation of QR-PC mixture in plasma samples without any significant interferences and matrix effects where the estimated recovery values were in the range of 97.64 %–103.58 % alongside low RSD values ≤ 1.27 %. Significance The designed SWV methodology suggests the first-ever analytical approach for simultaneous determination of QR and PC. Furthermore, the sustainability of the proposed method was estimated via four metrics (AGREE, AGREEprep, RGB 12 algorithm and GSST), highlighting its superiority over the reported methods in terms of using safer chemicals and solvents, simpler analytical procedure and sample preparation steps, as well as improved overall greenness. The significance of the method sits in its prospective to present a sustainable, sensitive, and consistent tool for analysis of QR-PC drug combination.