This paper presents a comprehensive timing optimization methodology for power-efficient high-resolution image sensors with column-parallel single-slope analog-to-digital converters (ADCs). The aim of the method is to optimize the read-out timing for each period in the image sensor’s operation, while considering various factors such as ADC decision time, slew rate, and settling time. By adjusting the ramp reference offset and optimizing the amplifier bandwidth of the comparator, the proposed methodology minimizes the power consumption of the amplifier array, which is one of the most power-hungry circuits in the system, while maintaining a small color linearity error and ensuring optimal performance. To demonstrate the effectiveness of the proposed method, a power-efficient 108 MP 3-D stacked CMOS image sensor with a 10-bit column-parallel single-slope ADC array was implemented and verified. The image sensor achieved a random noise of 1.4 e-rms, a column fixed-pattern noise of 66 ppm at an analog gain of 16, and a remarkable figure-of-merit (FoM) of 0.71 e-·nJ. The sensor utilized a one-row read-out time of 6.9 µs, an amplifier bandwidth of 1.1 MHz, and a reference digital-to-analog converter (DAC) offset of 512 LSB. This timing optimization methodology enhances energy efficiency in high-resolution image sensors, enabling higher frame rates and improved system performance. It could be adapted for various imaging applications requiring optimized performance and reduced power consumption, making it a valuable tool for designers aiming to achieve optimal performance in power-sensitive applications.