The 899 Panigale's chassis continues the innovative Monoscocca concept: different components have been integrated to give shape to a single compact and lightweight element that also enhances the rider's posture to perfect the riding position. The monocoque structure in cast aluminium for increased strength uses the Superquadro engine as a structural element and allows Ducati Superbikes to be lightest-in-class. The monocoque frame is fixed directly to the cylinder head, and at its front are two aluminium bushings inserted with the steering tube bearings. In addition to performing the traditional function of a frame, the monocoque also acts as an airbox. Housed inside it, in addition to the air filter, are the throttle bodies and fuel circuit complete with injectors; and the bottom of the steel tank (lighter by 1.9% compared to previous generation Superbikes) becomes its cover when mounted in place.

The 899 Panigale features a weight distribution equivalent to 52% at the front and 48% at the rear without the rider. The ratio then becomes an optimal 50:50 when the rider is on the seat to guarantee absolute stability and handling. To achieve this optimal configuration, solutions were implemented to allow a concentration of the weights at the front: the engine has come forward, the exhaust system is placed under the engine, and the rider's position is advanced.