The crash happened before midnight on Tuesday in a southbound lane near Floral Avenue.
California Highway Patrol officers say the motorcyclist was rear-ended by a silver Nissan and thrown onto the highway.
The bike was then struck several times by passing vehicles. Officers say four vehicles were involved, including a semi-truck.
The motorcyclist was taken to Community Regional Medical Center in downtown Fresno.
No one else was injured.
The CHP is investigating whether the Nissan driver was under the influence at the time of the crash.
Southbound Highway 99 was closed for about 20 minutes while officers cleared the scene.