In the event of a collision, several safety devices come to life in the 2006 Mercedes R-Class. Dual stage front airbags, side impact airbags for the front seats, and curtain airbags for all three rows are standard, while second-row side airbags are optionally available. Another optional feature is Neck-Pro, a head restraint system that activates during rear-end collisions. When the R-Class is hit from behind, these restraints move forward and upward to protect occupants from whiplash injuries. Another system called Pre-Safe prepares the vehicle for an imminent collision by pre-tensioning the seatbelts, electronically optimizing the seat positions, and closing the sunroof. Also onboard are a rollover sensor, a tire pressure monitor, and stability control.

One feature that provides both stability and comfort is the Adaptive Damping System. Solenoids in the shocks modify the rebound and compression settings when body roll is detected. The system is set for four stages– stage 1 features soft compression and rebound for comfort, stage 2 automatically works with stage 3 to adjust compression and rebound for maximum stability depending on road conditions and the way the R-Class is driven, and stage 4 hardens both for better cornering at speed. The system allows for some driver control, with selectable Auto, Sport, and Comfort modes.