It happened just after 5 p.m. at the intersection of Barbour Store and Old Stage roads, south of Garner.
The Highway Patrol says the motorcycle driver, identified as 34-year-old Kerry Fletcher, crossed the center line and sideswiped two cars. Then he hit a third car and a pickup truck head-on.
Fletcher died. His wife, 29-year-old Stephanie Fletcher, was taken in critical condition to WakeMed, where she later died.
People in the vehicles were treated at the scene.