Thieves broke into the Henry Moore Foundation in Perry Green in Hertfordshire, north of London, on Thursday evening and stole the 1969-70 work A Reclining Figure, possibly for scrap value.
Two vehicles entered the courtyard of the museum and three men loaded the sculpture, measuring more than 11 feet (3.3 metres) long and weighing 2.1 tonnes, on to the back of a truck, using a crane.
The second vehicle used by the men is thought to have been a Daihatsu four-wheel drive with spotlights.
The "audacious" theft was captured on CCTV, police said. Despite the sculpture's high value in the art world, the melted-down metal might fetch only $8800 on the open market.
"The [Henry Moore] foundation is offering a substantial reward for information leading to its recovery ... We are fearful it is possibly going to be sold for scrap, which would be a travesty"
Detective Sergeant Graeme Smith,
Detective Sergeant Graeme Smith of Hertfordshire Police said: "This is a very valuable statue and we are working closely with the Henry Moore Foundation to ensure its safe return.
"The foundation is offering a substantial reward for information leading to its recovery ... We are fearful it is possibly going to be sold for scrap, which would be a travesty."
Chief Inspector Richard Harbon described the sculpture as a "national treasure" and said officers were investigating whether it was stolen to order. The sculpture has been valued at more than $5.3 million.
The investigation involves liaison with the Metropolitan Police's Fine Arts Squad.
Moore, who died in 1986 aged 88, was widely regarded as Britain's best 20th-century sculptor. He moved to Perry Green with his family after his home in London suffered bomb damage and lived and worked there for the rest of his life.
Last month, Moore's Mother and Child - a marble sculpture measuring less than nine inches (22.8 centimetres) - sold for just under $1.9 million at auction, a record for one of his carvings.
Gareth Spence, a spokesman for the foundation, said it was the first such theft there. The weight of sculptures had been thought to be deterrent enough for would-be thieves.