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  1. Electrochemical biosensors promise a simple method to measure analytes for both point-of-care diagnostics and continuous, wearable biomarker monitors. In a liquid environment, detecting the analyte of interest must compete with other solutes that impact the background current, such as redox-active molecules, conductivity changes in the biofluid, water electrolysis, and electrode fouling. Multiple methods exist to overcome a few of these challenges, but not a comprehensive solution. Presented here is a combined boron-doped diamond electrode and oil–membrane protection approach that broadly mitigates the impact of biofluid interferents without a biorecognition element. The oil–membrane blocks the majority of interferents in biofluids that are hydrophilic while permitting passage of important hydrophobic analytes such as hormones and drugs. The boron-doped diamond then suppresses water electrolysis current and maintains peak electrochemical performance due to the foulant-mitigation benefits of the oil–membrane protection. Results show up to a 365-fold reduction in detection limits using the boron-doped diamond electrode material alone compared with traditional gold in the buffer. Combining the boron-doped diamond material with the oil–membrane protection scheme maintained these detection limits while exposed to human serum for 18 h.