Accurate, timely, and sensitive diagnosis is the first step in appropriately treating disease. The development of diagnostics that can be used in non-hospital and point-of-care (PoC) settings is key for democratizing access to disease diagnosis and treatment when it is most effective. The application of PoC diagnostics in early disease detection is often limited due to insufficient sensitivity for the short time frames and limited resources available in these settings. To overcome these challenges, this thesis presents the synthesis, characterization, and application of catalytic nanomaterials for signal amplification and enhanced sensitivity in PoC diagnostic platforms. The nanomaterials developed here span a broad size regime from 1.5 nm clusters of atoms to 300 nm diameter particles and have been demonstrated for use in both in vitro and in vivo biosensing platforms. The platinum and gold nanomaterials exhibited robust and efficient peroxidase-like activity in their ability to oxidize chromogenic substrates in the presence of hydrogen peroxide to generate additional colored signals that could be used for amplification of disease detection, even after exposure to harsh conditions such as elevated temperatures. The larger catalytic nanomaterials were employed as extraordinarily stable and highly amplifying labels in a simple paper-based lateral flow assay (LFA). The nanocatalyst-labeled LFA surpassed the sensitivities of both commercial and published reports to date for paper-based detection of p24, one of the earliest and most conserved biomarkers of HIV. The smaller catalytic nanoclusters were efficiently renally cleared and were deployed in a modular nanosensor platform to monitor disease-associated protease activity in vivo. Catalytic activity of cleared gold nanoclusters in collected urine provided a simple, sensitive, and rapid colorimetric urinary readout of disease state. The clinical utility of both platforms presented here was investigated through detection of acute phase HIV in clinical human plasma samples using the nanocatalyst-labeled LFA, and successful non-invasive detection of tumors in a mouse model of colorectal cancer using the protease-nanosensors with colorimetric urinary readout. This thesis demonstrates the broad applicability and versatility of catalytic nanoparticle amplification for use in disease detection. A pipeline for further development of both sensing platforms for detection of other biomolecules at the PoC is presented.