The Dutch royal, 44, was in a skiing accident in February 2012 that left him with severe brain damage and caused him to fall into a coma.
The royal palace released a statement on Monday, confirming the tragic news.
"Prince Friso died from complications that arose as a consequence of the brain damage caused by oxygen deprivation following his skiing accident," read the statement.
The father-of-two, who leaves his wife Princess Mabel and their two daughters Luana and Zaria, passed away at the Palace Huis ten Bosch in the Hague where he was being cared for. He had remained in a state of "minimal consciousness" since the accident.
Prince Friso was skiing off-piste in Lech, Austria when he was buried in an avalanche and trapped under the snow for 15 minutes. His brain was starved of oxygen while rescuers tried to locate him. Emergency workers were able to reach Prince Friso quickly and airlift him to safety as he was wearing a beeper.
An MRI scan was performed shortly after the accident which indicated that the prince had suffered large amounts of brain damage due to a lack of oxygen, which also resulted in a heart attack.
Prince Friso was initially cared for at The Wellington hospital in London, but was transferred back to the Netherlands last month. His wife is said to have spent her 45th birthday on Sunday at his bedside.
King Willem-Alexander and Queen Maxima, who were inaugurated in April, are said to be on their way home from a holiday in Greece to be with the family.