We present a system-level model for an ambient temperature-compensated CMOS MEMS Thermal Flow (C2MTF) sensor. The system-level model is first validated by a computational fluid dynamics (CFD) model and is further used for a fully coupled simulation between the microstructure, heat transfer, and interface circuits. Correspondingly, a monolithically integrated C2MTF sensor is designed and optimized using a 0.18 μm 1P6M CMOS MEMS technology. The designed System on Chip (SoC) C2MTF sensor has a flow range of -10~10 m/s, and its highest sensitivity is 0.274 V/(m/s) with a system power consumption of less than 3.6 mW. In comparison with the more than 50% output drift for the uncompensated counterpart, the output drift of the currently designed C2MTF sensor is reduced to 7% under an ambient temperature of 0~50℃. In addition, based on the proposed system-level model, the additional optimizations show that the output drift can be greatly reduced to 0.5%, by arranging another on-chip overheated temperature-regulating resistor Rc in the future, delicately.