The second-generation Mercedes-Benz Sprinter (chassis code W906, also designated NCV3) premiered in 2006, co-developed alongside the first-generation Volkswagen Crafter. Featuring dynamic vertical headlights and a bold front grille, the W906 covered gross vehicle weight ratings from 3.0 to 5.0 tonnes. It introduced Adaptive ESP stability control as standard safety equipment across all body variants.

Powertrains included 2.1-liter OM646 and OM651 four-cylinder turbodiesels, a smooth 3.0-liter V6 CDI turbodiesel producing 190 hp, 3.5-liter gasoline V6s, and compressed natural gas (NGT) engines. Available drive layouts comprised rear-wheel drive and factory 4x4 all-wheel drive. A comprehensive 2013 facelift introduced a upright front grille, LED daytime running lights, and Collision Prevention Assist.