Catalytic electrochemical sensors enable indirect electrochemical transduction of target-receptor physicochemical interactions within the recognition layer, through catalytic conversion of the bound target, followed by electroanalysis of the liberated detectable product (or underlying redox mediator) on the working electrode. In contrast, electrocatalytic sensors catalyze a direct electrochemical reaction between the electroactive target and the working electrode, resulting in direct electroanalysis of the target analyte. Enzymes are bioreceptors with high catalytic efficiency for specific conversion of their substrates and have been conventionally used in biocatalytic sensors for sensitive yet indirect electroanalysis of non-electroactive targets like organophosphorus (OP) compounds, glucose, lactate, alcohol, ketone bodies, and urea. Moreover, certain electroactive targets like nitroaromatic OP pesticides, uric acid, and ascorbic acid require high applied potentials for their electrocatalytic reactions, thus making their enzymatic conversion and indirect electroanalyses more thermodynamically favorable, while affording minimal interference from secondary electrochemical reactions. Recently, synthetic catalytic receptors, popularly termed as nanozymes when the catalyst is nanostructured, have emerged as rugged biomimetic substitutes to biological enzymes, yielding superior storage and operational stability, along with higher temperature and pH resiliency. Their robust performance in dynamic and uncontrolled field environments make them ideal candidates to realize extended and unaided operation of remote, handheld, and wearable electrochemical sensors. Another key consideration in developing electrochemical sensing systems for extended field operation are their energy requirements, which has ushered the emergence of self-powered potentiometric enzymatic biosensors, that considerably reduce the energy consumption versus conventional amperometric/voltammetric enzymatic biosensors. This galvanic cell-inspired sensing approach virtually enables energy-autonomous operation, and sometimes even oxygen-independent operation, of enzymatic biosensors with the appropriate selection of redox mediator for enzyme regeneration, and a joint counter/reference electrode bearing high charge capacity and an appropriate formal potential to drive the electrochemical reaction of the enzymatic reaction product (or regeneration of the enzyme electrode mediator). When targets possess sufficient electroactivity, catalytic electrochemical sensors are often replaced with electrocatalytic sensors, to enable direct electroanalysis of the target (instead of the enzymatic reaction product). This approach is usually subject to higher interference due to relatively higher applied potentials required to drive such electrochemical reactions. However, it is the common sensing approach for targets that exhibit low catalytic conversion efficiency (or low electroactivity of their enzymatic reaction (by)products). Hence, nanomaterials or redox mediators with high electrocatalytic activity can play a vital role in reducing the applied potential required for such direct electrochemical reactions, while enhancing the faradaic reaction kinetics for improved current sensitivity of sensor response. Opioids and other narcotics are common candidates for direct electrooxidation, apart from other electroactive analgesics like acetaminophen, and neurotransmitters like dopamine and serotonin. However, electrode fouling is a significant concern while sensing such aromatic/phenolic electroactive targets due to strong hydrophobic interactions of their reaction products with compatible working electrodes (usually carbon-based). In this complicated scenario, protective antifouling membranes or periodic electrochemical regeneration are employed to prolong sensor operational stability. Redox mediator-tagged electrochemical aptamer-based sensors are promising alternatives to avoid the fouling limitations of direct target electrooxidation, and enable non-destructive, reversible, extended, and continuous monitoring in biological fluids. Accordingly, this dissertation aims to introduce and explain the rationale behind optimal combination of a catalytic/electrocatalytic material, antifouling/permselective membrane, and the corresponding electrochemical transduction mechanism for rapid and extended quantification of a wide spectrum of health biomarkers, drugs, and environmental threats across multiphasic samples. The development of handheld, wearable, implantable, and remote submersible electrochemical sensing systems will be discussed across emerging health and environmental monitoring applications, with a focus on chemical warfare agents, nitroaromatic OP pesticides, toxic ions, opioids, and human metabolites.