He was 87.
The founder of the Las Vegas Sands casino company, Adelson was known for his support of conservative causes and Israel.
He was a significant backer of US President Donald Trump and Israeli Prime Minister Benjamin Netanyahu.
His death was caused by complications related to his treatment for non-Hodgkin's lymphoma, the Las Vegas Sands company said in a statement.
In a statement, former US president George W Bush said he mourned the passing of a "friend".
"He was an American patriot, a generous benefactor of charitable causes, and a strong supporter of Israel," Bush said. "He will be missed by many - none more than his beloved family."
Israeli Prime Minister Benjamin Netanyahu said Adelson and his Israeli-born second wife Miriam "contributed endlessly to strengthening the Jewish people and the Jewish state".
"He was a wonderful friend to us personally and an incredible champion of the Jewish people, the Jewish state and the alliance between Israel and America," he said.