Keselamatan dari Mercedes-Benz S-Class adalah sebagai berikut:
| Varian | Mercedes-Benz S-Class S 450 L | Mercedes-Benz S-Class Maybach S 560 |
| 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 |
| 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 |
| Sistem kontrol traksi | ||
| Vehicle Stability Control (VSC) | ||
| Child safety lock | Y | Y |
| ISOFIX | ||
| Security alert | ||
| Immobilizer | Y | Y |
