The data redundancy and dynamic range (DR) of quanta image sensor (QIS) are different under different oversampling bit-depth, and the requirements for readout circuit are also different. The reading noise introduced in the imaging process of QIS is studied, and the mathematical model of QIS imaging is optimized. Under the constraints of DR and offset tolerance, the optimal bit-depth of sub-pixel oversampling is obtained. The simulation results show that when the imaging bit-depth of the QIS is 12 bit and the equivalent full well capacity is 4095 electron, the optimal bit-depth of sub-pixel oversampling is 3. In order to ensure that the interval bit error rate is less than one thousandth, the readout circuit offset should be less than 0.22 electron. According to the sampling strategy, a flash low noise readout circuit based on multiplexing structure is designed. Compared with the traditional flash analog-to-digital converter (ADC), the number of ADC comparators is reduced by 4, and the power consumption is reduced by 17.5% when the sampling frequency is 10 MSa/s; when the sampling frequency is 1 MSa/s, the power consumption of ADC is 116 nW and the offset of ADC is 0.196 electron.