The parents, both aged in their 20s, and their two daughters, both aged under three, were travelling in a Fiat car on the A801, near the Lathallan roundabout where it joins with the M9 motorway.
Police said their car had apparently crossed into the path of oncoming traffic.
Superintendent Iain Murray, Police Scotland’s head of road policing, said: “This was a tragic collision which sadly killed all occupants of the car.”
Their black Fiat hatchback collided with an aggregates lorry just after 2pm in a crash which members of the emergency services described as a “horrific” scene.
Police have yet to identify the family but it is believed they lived in West Lothian.
Crash investigators were at the site last night and the road between the roundabout and the Bowhouse roundabout junction with the B825 remained closed.
Firefighters had to cut from the Fiat vehicle one of the four people who died, it emerged.
Sergeant Andrew Thomson, of Police Scotland, said: “This was a two-vehicle fatal road collision. There was a serious collision between a rigid tipper lorry and a hatchback Fiat car.
“The four occupants of the Fiat car were pronounced dead at the scene. This included a mother, a father and two pre-school children.
“The truck driver was badly shaken but uninjured.
“Our investigations are at an early stage but we are asking anyone who saw a black Fiat car or a tipper lorry on this road to get in touch.”
A farmer who owns the adjoining field, who did not want to be named, said: “People fly up and down the road, but I would not say it’s dangerous.
“I just saw the road closed when I came along the field and I saw the flashing lights.”
Pictures from the scene showed at least five emergency vehicles, an upright lorry and what appeared to be blue tarpaulin covering the car.
The A801 links the M9 with the M8 near Whitburn in West Lothian and has been the scene of numerous crashes.
Linlithgow and East Falkirk MP Michael Connarty, who has campaigned for 20 years for the A801 to be upgraded to dual carriageway, described it two years ago as “probably the most dangerous road in Scotland when it is not snowing”.
He told a House of Commons committee on lorry charging plans: “As I have been arguing for 20 years, it is time that the government of Scotland and the UK government put their hands in their pockets to get rid of this nonsense of having a major road network with a bad ‘A’ road.”
He told The Scotsman in 1993: “It’s of critical importance. If nothing is done it will only be a matter of time before someone is killed.”
In 2012, a 40-year-old man died after his Mercedes E220 collided head on with an articulated lorry.
Last year, a lorry driver died on the road when his vehicle overturned.