More than 100 others have been injured following the blaze at Pulse in the town of Kocani at around 2.35am on Sunday.
The flames broke out while a local pop band was performing, interior minister Panche Toshkovski told a news conference.
Fireworks were set off inside the venue, which used to house a carpet warehouse, causing the roof to catch fire, according to reports.
Video from the event shows the band playing on stage when two flares go off either side of them and shoot towards the ceiling.
Health minister Arben Taravari said 118 people were taken to hospital, with neighbouring countries also offering medical assistance.
“All our capabilities have been put to use, in a maximum effort to save as many lives as possible of the young people involved in this tragedy,” Mr Taravari told reporters.
Some are being treated at Kocani General Hospital, where relatives have gathered to await more information, newspaper Nova Makedonija said.
Broadcaster MRT reported that 27 people were being treated for severe burns at Skopje City Hospital, with another 23 at the Clinical Centre.
The country’s prime minister Hristijan Mickoski wrote in a statement on X: “This is a difficult and very sad day for Macedonia. The loss of so many young lives is irreparable, and the pain of the families, loved ones and friends is immeasurable.”
He promised the government would do “everything in their power to at least slightly alleviate their pain”.
Police and forensic investigators cordoned off the scene on Sunday, with authorities saying evidence would be collected for state prosecutors.
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The US ambassador to North Macedonia Angela Aggeler also posted on X, saying her “heart breaks this morning for the many victims in last night’s fire at a nightclub in Kochani”.
“Our deepest condolences go to the victims and their loved ones at this awful time, and wishes for a speedy recovery to those who were injured,” she said.
Various leaders offered their condolences, including Albanian Prime Minister Edi Rama and Ukrainian President Volodymyr Zelenskyy.
“I wish those who were injured a speedy recovery. Ukraine mourns alongside our North Macedonian friends on this sad day,” Mr Zelenskyy wrote on X.
