This paper presents a low-noise analog front end (AFE) with interstage systematically ambient interference cancellation for a pulse oximeter, which is suitable for clinical oxygen saturation (SPO2) detection with a low perfusion index. The fully differential implementation is adopted to have a better rejection performance of common mode interference and noise. Firstly, the proposed interstage systematically ambient interference cancellation is placed in the two gain stages to decrease low frequency noise in the bandwidth of interest (0.1–20 Hz), so that the larger signal-to-noise ratio (SNR) can be achieved to increase the detection accuracy of this system. Secondly, due to the additional gain stage compared with traditional implementation, the current-reuse OTA is employed to have better noise and power efficiency. Thirdly, the auto zero technique is utilized in the LED Driver to decrease the offset voltage and acquire a larger dynamic range (DR) in the low frequency bandwidth of interest. This PPG AFE chip is designed and fabricated in a 180 nm standard CMOS process. The receiver (RX) of this AFE consumes 220 μW from a 1.8 V supply, and the power consumption of the transmitter (TX) is 60 μW from a 3 V supply. The measurement results show that the input-referred noise current of 2.3 pA/sqrt(Hz) is achieved in RX and 110 dB peak DR is obtained in TX.