Noble metal nanoparticles (NMNPs) have become firmly established as effective agents to detect various biomolecules with extremely high sensitivity. This ability stems from the collective oscillation of free electrons and extremely large electric field enhancement under exposure to light, leading to various light-matter interactions such as localized surface plasmon resonance (LSPR) and surface-enhanced Raman scattering. A remarkable feature of NMNPs is their customizability by mechanisms such as particle etching, growth, and aggregation/dispersion, yielding distinct color changes and excellent opportunities for colorimetric biosensing in user-friendly assays and devices. They are readily functionalized with a large variety of capping agents and biomolecules, with resultant bioconjugates often possessing excellent biocompatibility, which can be used to quantitatively detect analytes from physiological fluids. Furthermore, they can possess excellent catalytic properties that can achieve significant signal amplification through mechanisms such as the catalytic transformation of colorless substrates to colored reporters. The various excellent attributes of NMNP biosensors have put them in the spotlight for developing high-performance in vitro diagnostic (IVD) devices that are particularly well-suited to mitigate the societal threat that infectious diseases pose. This threat continues to dominate the global health care landscape, claiming millions of lives annually. NMNP IVDs possess the potential to sensitively detect infections even at very early stages with affordable and field-deployable devices, which will be key to strengthening infectious disease management. This has been the major focal point of current research, with a view to new avenues for early multiplexed detection of infectious diseases with portable devices such as smartphones, especially in resource-limited settings.In this Account, we provide an overview of our original inspiration and efforts in NMNP-based assay development, together with some more sophisticated IVD assays by ourselves and many others. Our work in the area has led to our recent efforts in developing IVDs for high-profile infectious diseases, including Ebola and HIV. We emphasize that integration with digital platforms represents an opportunity to establish and efficiently manage widespread testing, tracking, epidemiological intelligence, and data sharing backed by community participation. We highlight how digital technologies can address the limitations of conventional diagnostic technologies at the point of care (POC) and how they may be used to abate and contain the spread of infectious diseases. Finally, we focus on more recent integrations of noble metal nanoparticles with Raman spectroscopy for accurate, noninvasive POC diagnostics with improved sensitivity and specificity.