The acquisition of high-voltage signals from sensors and actuators in an internal-combustion engine is often required for diagnostic purposes or in the case of conversion to alternative fuels, such as hydrogen, natural gas, or biogas. The integration of electronic interfaces and acquisition circuits in a single device provides benefits in terms of component-count reduction and performance. Nonetheless, the high voltage level of the involved signals makes on-chip design challenging. Additionally, the circuits should be compatible with the CMOS technology, with limited use of high-voltage options and a minimum number of off-chip components. This paper describes the design and the implementation in 350 nm CMOS technology of electronic interfaces and acquisition circuits for typical high-voltage signals of automotive context. In particular, a novel co-design of dedicated voltage clamps with electro-static discharge (ESD) protections is described. The proposed circuits require only a single off-chip resistor, and they are suitable for the acquisition of signals with peak voltages up to 400 V. The measured performance of the silicon prototypes, in the [−40 °C, +125 °C] temperature range, make the proposed electronic interfaces suitable for the automotive domain.