During the course of its development, the new E-Class was subjected to more than 150 high-speed crash tests and a total of more than 17,000 realistic crash simulations. The crumple zone principle invented by the Mercedes safety pioneer Béla Barényi has been continuously improved by the engineers in Sindelfingen. The front-end deformation zone of the Mercedes-Benz E-Class acts on four independent levels, and is even more effective than before. The increased use of highest-strength steel alloys also helps to ensure that the bodyshell is able to withstand high impact forces. Around 72 percent of all the body panels are made from these high-tech steels - yet another unrivalled figure in passenger car development.

With seven airbags as standard, belt tensioners, belt force limiters, crash-responsive head restraints and ISOFIX child seat attachments, the new Mercedes-Benz E-Class has even more extensive safety features than the preceding model. Another new feature is the active bonnet, which is a continuation of many years of commitment to pedestrian protection on the part of Mercedes-Benz. It is standard equipment in the new E-Class. In the event of an impact, a system of springs raises the rear section of the bonnet by 50 millimetres within fractions of a second, thereby increasing the available deformation space. Thanks to the cleverly conceived mechanism, the driver is able to reset the active bonnet to its normal position himself, without visiting a workshop.

Another standard feature is the preventive occupant protection system PRE-SAFE®. In potentially hazardous situations this reflexively activates precautionary protective measures for the vehicle occupants, so that the seat belts and airbags are able to fulfil their protective function to the full during an impact.