The IS 250's 2.5-liter V6 engine delivers 204 horsepower at 6,400 RPM and 185 lb.-ft. of peak torque at 4,800 rpm. The Lexus IS 350's 3.5-liter V6 offers a more potent 306 horsepower at 6,400 RPM and 277 lb.-ft. of torque at 4,800 rpm. The IS 350 RWD model can accelerate from zero-to-60 mph in just 5.3 seconds. Both engines employ dual Variable Valve Timing with intelligence (VVT-i), which controls timing on both the intake and exhaust camshafts.

Aside from its larger displacement, the 3.5-liter V6 also differs in that it augments the direct fuel injection with port fuel injectors. In light- and medium-load conditions, these additional injectors help produce a precise burn, optimizing power and efficiency. A dual exhaust system reduces backpressure at higher engine speeds.

An advanced six-speed automatic transmission with steering-wheel-mounted paddle shifters is standard on the Lexus IS 350 models and the IS 250 AWD. The IS 250 RWD comes standard with a crisp-shifting six-speed manual transmission, with the paddle-shift automatic offered as an option.