A westbound 2005 Ford Explorer crossed the center line, colliding with an eastbound 2005 Toyota 4Runner, the State Patrol said.
One of the victims, a 39-year-old man, was trapped inside the burning Explorer when troopers arrived at about 1 p.m.
The Explorer's driver, a 27-year-old woman, was ejected from the vehicle and taken to Seattle's Harborview Medical Center with severe leg injuries, Lt. Clint Casebolt said.
A 3-year-old girl and a 9-month-old girl were pulled from the Explorer by witnesses before troopers reached the scene. The 3-year-old was transported to Harborview with head injuries; the baby was treated at Olympic Memorial Hospital in Port Angeles, Casebolt said.
All the occupants of the Ford Explorer were believed to be residents of the Port Angeles area.
A 43-year-old man driving the Toyota was taken to Olympic Memorial, where he died. A 7-year-old girl from that vehicle was transported to Harborview, where she also died, Casebolt said.
That vehicle was registered in Beaverton, Ore.
A 3-year-old boy and a 35-year-old woman from the Toyota were taken to Olympic Memorial for treatment of their injuries.
U.S. 101 was closed until 6:23 p.m.
The names of the victims were not immediately released pending notification of relatives.