The Lexus LS 460 provides one of the most advanced and comprehensive integrations of vehicle-safety technology today. New Active Front Headrests on all models are designed to help mitigate whiplash injury in a rear collision. Active safety features include the Vehicle Dynamics Integrated Management (VDIM) system, which by itself integrates and manages the Electronically Controlled Brake (ECB) system, Electronic Power Steering (EPS), Vehicle Stability Control (VSC), Anti-lock Braking System (ABS), Electronic Brake-force Distribution (EBD), and engine torque via the electronically controlled throttle.

Taking input from an array of sensors in the vehicle, VDIM anticipates the onset of a vehicle skid or slide while cornering, and it then helps correct the condition with a combination of braking, throttle, and steering control in a way that is essentially transparent to the driver. The VDIM system gathers data from more sources - processed earlier and more quickly than in previous dynamic handling systems - to help make operation in the Lexus LS 460 even more seamless and effective. If it becomes necessary to extricate the car from deep snow or other difficult conditions, such as mud or sand, the "TRAC off" switch may be useful to turn off the VSC.

The Lexus LS 460 is standard-equipped with eight airbags, including side curtain airbags, front seat-mounted side airbags and knee airbags for the driver and front passenger. Rear seat-mounted side airbags are also available. Standard xenon high-intensity discharge (HID) headlamps provide superior road illumination. The standard Adaptive Front lighting System (AFS) helps to illuminate a turn or curve as the driver steers into it.

The Lexus LS 460 and Lexus LS 460 L models offer Advanced Parking Guidance System (APGS) to assist with parallel and back-in parking. Once the driver has correctly positioned the car and identified the desired parking space via the navigation screen, APGS uses the rear back-up camera, parking sonar sensors and electric power steering system to guide the car into the space. The driver controls vehicle speed via the brake.