An image sensor may include an array of pixels, and analog and digital circuitry. The pixels in the array may generate image signals in response to incident light. The image sensor may also include power supply circuitry and corresponding voltage rail structures that provide voltage levels to operate the pixel array, the analog circuitry, and the digital circuitry. The power supply circuitry may provide a low voltage, a high voltage, and an intermediate voltage power rail. The analog circuitry may operate in a voltage level domain defined by voltages between an intermediate voltage level and a high voltage level. The digital circuitry may operate in a voltage level domain defined by voltages between a low voltage level and the intermediate voltage level. In such a configured, analog and digital circuitry may both be provided with low-voltage transistors that are more area and power efficient and that are more scalable.