To determine the effect of toxicants on an organ, a two-fold approach has been taken: an organotypic system (Organ-on-Chip) was used to model the organ and its system, and electrochemical sensors were used to simultaneously measure multiple biomarkers. Current electrochemical analyses using enzymes are limited by their inability to monitor cellular responses when compounds with inherent redox activity are present. Several common chemicals fall into this category including, acetaminophen (APAP), ascorbic acid (AA), and uric acid (UA). In this work, a multianalyte electrochemical biosensor array monitoring the changes of glucose, lactate, glutamate, and acetylcholine in the presence of an electroactive interferent is reported. To mitigate interference, two methods were utilized. Specifically, an osmium-based redox polymer was developed that mediates the electron transfer from an oxidase enzyme to the electrode. By taking advantage of this osmium polymer’s oxidation potential, a lower electrode bias was employed to avoid the bulk oxidation of the interferent, and therefore diminish interference. Another method electropolymerizes m-phenylenediamine on an electrode to make a size exclusion polymer (poly m-phenylenediamine). This polymer prevents larger molecules such as the interferents from reaching the electrode surface and being oxidized, and therefore detected. Both of these sensors maintained excellent sensitivity, demonstrated increased selectivity of the analyte over the interferent, and exhibited longevity. Furthermore, these low-interference tools provided a high-resolution platform for improved analyses in several potential applications including, toxicity studies on model organs (UA is an electroactive metabolite), clinical studies (APAP interferes with glucose meters), and in vivo studies on the brain (AA is an endogenous interferent).