The crash happened late Friday on Jerseyville Road near Paddy Greene Road.
Police say the three men and one 14-year-old girl will recover but are not releasing names of those involved in the crash until all next of kin have been notified.
Two men were killed in the crash. One at the scene, the other died a short time later at Hamilton General hospital.
Two other men were taken from the crash site to the General with serious injuries.
Another man was taken to St. Joseph’s Hospital with minor injuries. A 14-year-old girl also in the vehicle was transported to McMaster Children’s Hospital with minor injuries.
"lt appears someone was in the wrong lane," Hamilton police Staff Sgt. Mike Worster told CBC Hamilton.
"The scene was pretty chaotic when officers arrived," Worster said. "There were a lot of injured parties all over the place and the cars were total write-offs. A lot of damage."
Worster said alcohol is not believed to be a factor in the crash, but speed might be.
Donna Stechey lives about a kilometre away from the crash site, and is on that stretch of road almost every day. She heard the sirens Friday night.
"When I heard the news, my heart sank," she told CBC Hamilton on Saturday morning.
"It's a very dangerous road — it's not just that people go super fast, it's the twists and the blind turns."
She says she has seen the danger firsthand.
A couple of summers ago she says she was stopped on the side of the road with a friend while biking. They saw a truck come off a road to turn onto Jerseyville and miss a fire truck by inches.
"I wouldn't have really understood the blind spot unless I stood there that day. The air just came out of our bodies."
Worster said the road can be dangerous because it has very hilly curves and poor lighting. It's also bordered by a conservation area and deer wander through the area.