In this work, for the first time, the direct usability of natural products, catechins (CT) and cocoa powder (CO), as electrochemical mediators able to modify a carbon black modified screen-printed electrode (SPE-CB) is proved, and, as proof of applicability, free (GSH) and total glutathione (GSH + GSSG) in blood samples is successfully determined. Noteworthy, the cocoa powder (naturally rich in catechins), dissolved in DMSO, was able to give rise to a useful highly redox-active catechol-quinone surface-confined system onto a carbon black nanoparticles modified screen-printed electrode (SPE-CB-CO – Cocoatrode), giving rise to a similar behaviour obtained with pure catechins (SPE-CB-CT). The electrodeposition process has been carefully studied, the resulting immobilized natural mediator (obtained using both CT and CO) features investigated, and the performance of the resulting sensors (SPE-CB-CT and Cocoatrode) tested and compared. Both modified electrodes (SPE-CB-CT and Cocoatrode) have a good inter-electrodes precision (RSD ip,a ≤ 4.2%, n = 3) and intra-electrodes repeatability (RSD ip,a ≤ 3.9%, n = 20), indicating a robust and stable ‘fabrication’ strategy. Finally, SPE-CB-CT and Cocoatrode have been employed for the detection of free (GSH) and total (GSH+GSSG) glutathione in blood samples, using differential pulse voltammetry decrease in the mediator's reduction peak (Δi %), as analytical signal. Analytical curves (R2 ≥ 0.998), for the GSH detection, have been determined both with SPE-CB-CT and Cocoatrode in the 2.5 × 10−8-6.0 × 10−5 M and 5.0 × 10−8-1.0 × 10−4 M concentration ranges, respectively. Limits of detections (LODs) were ≤2.6 × 10−8 M. GSH (free and total) determined in blood samples, by the proposed CT and CO sensors, showed a good intra-electrode repeatability (RSD ip,a ≤ 9.0%, n = 3), with good recoveries (from 88.3% to 117.7%). The values obtained were in agreement with a classical spectrophotometric method (GSH and GSSG concentration relative error between −4.7 and +9.8%). The SPE-CB-CT and the Cocoatrode platforms demonstrated high potentiality in sensing and biosensing scenario, opening new gates to the natural/food products employment as unconventional, eco-friendly and economically affordable analytical active tools.