The tragic incident saw a lorry collide with a car, and the car then crash into another HGV on the eastbound carriageway of the M62 between junction 36 (Goole) and junction 37 (Howden) at approximately 9:50am.
A 54-year-old man who was driving the car and a 53-year-old man driving one of the HGVs at the time of the collision, were sadly pronounced dead at the scene.
A 15-year-old girl was taken to hospital to receive medical treatment for injuries where she remains in a serious condition.
The families of those who have lost loved ones have been informed and are currently being supported by specially trained officers, Humberside Police said.
“Our team would like to thank the members of the public who came to the assistance of those involved in the crash,” police officers added.
Paul Jackson, who witnessed the aftermath of the crash, yesterday described the moment he and two other men helped to rescue a girl from the cab of a jack-knifed lorry.
"The truck was on fire and these two men smashed the window and pulled this girl out," he said. "They were absolute heroes."
"I saw this black smoke when I was driving so stopped to help. People were running towards the back of the car, which was on fire."
"The truck had jack-knifed to they had to climb onto the trailer to get to the cab. They saved her life. The fire was engulfing the truck."
A police investigation into the incident is ongoing, and officers are appealing to anyone who was driving in the area at the time and may have dashcam footage to come forward.
“We would also like to hear from anyone who saw the collision or the vehicles prior to the collision to call us on our non-emergency number 101 quoting log 110 of 6 April,” they said.