The present study was inspired by the HADRIAN project and aims at investigating the impacts of innovative Human-Machine Interface (HMI) prototypes on safety, driving performance and drivers’ perceptions using driving simulator and questionnaire data. For this purpose, driving simulator experiments were conducted within the framework of the project in order to test if HADRIAN HMI innovations are safer and more acceptable for the driver. More specifically, this study focuses on a driving simulator experiment that tested innovative HMI prototypes that enhance Automated Driving (AD) SAE Levels 2 or 3. An “HADRIAN-tailored” safety and impact assessment methodology was developed using special Key Performance Indicators (KPIs). Descriptive statistics for the aforementioned KPIs were created in order to perform comparisons and prove the safety and impact advancements.