A high-resolution tilt angle measurement system is presented in this paper. In this system, the measurement signal is amplified by two steps: (1) amplified by operational amplifier and (2) differential amplified by two MEMS-based inclinometers. The novel application not only amplifies the signal but, more importantly, substantially reduces the electrical interference and common-mode noise among the same circuit design. Thus, both the extremely high resolution and great long-term stability are achieved in this system. Calibrated by an autocollimator, the system shows a resolution of 2 arc sec. The accuracy is better than ±1.5 arc sec. The zero-drift error is below ±1 arc sec and ±2 arc sec in the short and long term, respectively.