The post office and newsagent in Crosshill was targeted in the early hours of Sunday morning.
Thieves made off with the safe, which contained a four-figure sum of cash.
A Police Scotland spokesperson said: “Police in the Scottish Borders are investigating following a break-in and theft in Chirnside.
“The incident happened sometime between 4am and 4.45am on Sunday, February 10 at a business in Crosshill.
“After entry was forced to the premises a safe containing a four-figure sum of cash was stolen and inquiries are ongoing to trace those responsible.
“Anyone with information is asked to come forward.”
The post office moved into the Crosshill premises four years ago from its former home at Chirnside Gallery in Roseberry Terrace.