Prince Friso, who was 44, was moved from hospital in London back to the Netherlands last month, but had since suffered complications.
He was hit by an avalanche in February 2012 and buried for 15 minutes.
King Willem-Alexander and Queen Maxima are said to be on their way home from a holiday in Greece.
“Prince Friso has died of complications related to the hypoxic brain injury, which he suffered as the result of his skiing accident in Lech, Austria on 17 February 2012,” a royal palace statement said.
Prince Johan Friso died on Monday morning in The Hague, the palace added.
The prince’s wife, Princess Mabel, is said to have spent her 45th birthday on Sunday at his bedside.
Shortly before becoming king on the abdication of Queen Beatrix, his elder brother, Willem-Alexander spoke in April of the “terrible situation” the family had lived with for more than a year.
Prince Johan Friso’s wife and Beatrix had been doing their best to be there for him every day “to give him a chance”, he said.
The prince had been skiing off-piste with friends in Lech when the avalanche struck.
An emergency beeper he was wearing enabled rescuers to find him but medical officials in Innsbruck said it took some time to revive him and he suffered “massive” brain damage. They said he had suffered a heart attack lasting some 50 minutes.
Prince Johan Friso was later flown to London for treatment at the private Wellington Hospital, which has a specialist neurological unit.
He was eventually discharged in July 2013 but remained in a “state of minimal consciousness”.
At the time, officials said he would spend the summer with his family at the royal palace in The Hague, with medical treatment provided by a specialist team.
Prince Friso was Beatrix’s second of three sons, but was no longer in line to the throne after his 2004 marriage to Mabel Wisse Smit, because of her earlier involvement with a notorious Dutch drug criminal.
Prince Johan Friso had worked for several years in London and the couple moved there after their marriage. He took up his last job as chief finance officer at Urenco in 2011, having worked previously in investment banking at Goldman Sachs.
Prince Johan Friso and Princess Mabel had two daughters, Luana and Zaria.
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