Silicon nanowire field effect transistors (nanoFETs) are low noise, low power, and ultrasensitive biosensors that are highly amenable to integration. However, using nanoFETs to achieve direct macromolecular detection in physiological buffers remains difficult due to Debye screening, nonspecific binding, and stringent functionalization requirements. We circumvent these difficulties using an indirect method of detecting biomolecular interactions, by translating a specific binding response into a pH change that can be detected by our nanoFETs. Using this approach, we demonstrate sensitive detection of enzyme-substrate interactions, DNA, and proteins. Our method paves the way for future development of universal, highly sensitive, miniaturized, and integrated nanosensors that can be applied to a wide variety of analytes.