They believe Escobar, who was one of the richest men in the world when he was killed by Colombian police, may have hidden cash and diamonds there. The safe, which weighs 600kg (1,325lb), has not been opened yet.
`Holy grail`
A worker who was tearing down one of the last remaining walls of the waterfront house found the metal safe in the foundations.
The new owners of the house, Christian de Berdouare and his wife, Jennifer Valoppi, said they would take it somewhere safe and "open it shortly".
"For us, this is the holy grail," owner Christian de Berdouare told local media. Escobar was known for keeping huge stashes of cash and jewels at his homes in Colombia.
Workers had already found one safe in the house shortly after demolition work began, but it disappeared before anyone could examine it.
The couple said they bought the house without knowing of its history.
When they found out it had belonged to the infamous Colombian drug baron, they decided to make a documentary about its demolition and the search for hidden treasure within.
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