Keselamatan dari Mercedes-Benz E-Class adalah sebagai berikut:
| Varian | Mercedes-Benz E-Class E 200 Avantgarde Line | Mercedes-Benz E-Class E 300 SportStyle Avantgarde Line | Mercedes-Benz E-Class E 350 AMG Line | Mercedes-Benz E-Class E 300 Coupe AMG Line | Mercedes-Benz E-Class AMG E 43 4MATIC | Mercedes-Benz E-Class E300e AMG Line | Mercedes-Benz E-Class AMG E 63 S 4MATIC+ |
| Peringkat Euro NCAP | |||||||
| Peringkat ASEAN NCAP | |||||||
| Jumlah airbag | |||||||
| Airbag kursi penumpang / utama | |||||||
| Airbag sisi depan / belakang | |||||||
| Airbag lutut | |||||||
| Pengingat sabuk pengaman | |||||||
| Active emergency braking system | |||||||
| Tire Pressure Monitoring System (TPMS) | Y | Y | Y | Y | |||
| Lane Departure Warning System (LDWS) | |||||||
| Lane Keeping Assist System (LKAS) | |||||||
| Collision avoidance system(CAS) | |||||||
| Anti-lock Braking System (ABS) | |||||||
| Electronic Brake-force Distribution (EBD) | Y | Y | Y | Y | Y | ||
| Sistem kontrol traksi | |||||||
| Vehicle Stability Control (VSC) | |||||||
| Child safety lock | Y | Y | Y | Y | Y | Y | Y |
| ISOFIX | |||||||
| Security alert | |||||||
| Immobilizer | Y | Y | Y | Y | Y | Y | Y |
