The artwork, titled "Two Laughing Boys," dates from 1626 and depicts two jovial youths with a large mug of beer.
The painting was stolen from the Hofje van Mevrouw van Aerden museum in the town of Leerdam in the early hours of Wednesday morning.
"Around 3:30 a.m. the alarm went off, and agents went straight to the museum," police said in a statement.
Officers were unable to locate the suspects, but noted that they'd likely broken into the small museum using the back door.
"After the museum's manager could grant access to the area and building, it emerged that the back door had been forced open and one painting had been stolen," the statement read.
Thieves taking advantage of pandemic
"Two Laughing Boys" has already been stolen from the museum before — most recently in 2011 and in 1988.
The first time, it took police three years to recover the centuries-old work. In 2011 police were able to track it down after six months when the burglars tried to sell it.
One art expert estimated "Two Laughing Boys" is worth €15 million ($18 million), Dutch broadcaster RTL Nieuws reported.
"Criminals know that major museums have sufficient security," the expert told RTL, adding that smaller regional museums tend to have fewer security measures.
"They probably concluded it's worth a lot of money, and it's relatively easy to steal."
It's the second painting to be stolen from a Dutch museum that was closed due to COVID-19 measures.
In March, thieves stole a Vincent van Gogh painting called "Parsonage Garden at Nuenen in Spring" from a museum located east of Amsterdam. The theft occurred on what would have been van Gogh's 167th birthday.
Frans Hals was a contemporary of fellow Dutch masters Rembrandt van Rijn and Vermeer in the 17th century. He was born in the 1580s in Antwerp and moved as a child to the city of Haarlem. He's best known for his painting "The Laughing Cavalier" and several life-size group portraits.