The 2008 Mercedes-Benz S-Class is largely unchanged following its redesign for the 2007 model year. Four rear-wheel-drive models are offered along with one that has Mercedes' 4Matic all-wheel drive. The S550 has a 382-hp 5.5-liter V8, as does the AWD S550 4Matic. The S63 has a 6.2-liter 518-hp V8. The S600 has a turbocharged 5.5-liter 510-hp V12, and the high-performance S65 has a 6.0-liter version of that engine with 604 hp. All come only with an automatic transmission; a 7-speed in S550/S550 4Matic and S63, a 5-speed in the S600 and S65.

The S-Class suspension automatically adjusts for firmness and load leveling. Available safety features include ABS, traction control, antiskid system, curtain side airbags, and front and rear side airbags. Mercedes' Pre-Safe system is also standard; it senses an impending collision and tightens the seat belts and applies additional braking force. Also included are Mercedes' Tele Aid assistance and its COMAND system, which incorporates a video screen and console-mounted "joystick" knob to control audio, navigation, phone, and other functions; it also accepts voice commands. The S63 and S65 are tuned by Mercedes' AMG high-performance division and include sport suspension, sport exhaust and seats, and specific trim.

Available features on S-Class include ventilated and massaging front seats, heated and ventilated rear seat, and keyless access and starting. Also offered is a rearview camera and Mercedes' Distronic Plus adaptive cruise control.