The collision happened on the A1079, between Wilberfoss and Barmby Moor, at about 1.15pm.
Officers are now at the scene, Humberside Police said.
The crash involved a black Peugeot 207, a white Renault Estate panel van and a white Ford Transit tipper truck.
A force spokesman said: "Two men suffered what are thought to be serious injuries.
"The road is currently closed and motorists are advised to avoid the area."