The crash happened at around 8pm on Tuesday night near the Jinnah restaurant between Flaxton and Barton-le-Willows.
A 44-year-old woman, nine-year-old girl and five-year-old boy travelling in the grey motorhome were pronounced dead at the scene.
A six-year-old boy was taken to hospital with a serious head injury and the 48-year-old man driving the motorhome was also seriously hurt.
None of those involved have yet been identified and police have not clarified their relationships to each other.
The driver of the HGV was not injured.
The road was closed between for several hours while emergency services worked at the scene. It re-opened at 6.45am today.
Anyone who witnessed the incident, has any dashcam footage or was travelling in the area at the time is asked to contact North Yorkshire Police.